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![Preface
We welcome the reader to this book on different
aspects of Early Vascular Aging (EVA), a concept that
has attracted considerable attention since it was first
described in 2008. A number of skilled authors have
contributed to provide a multifaceted description of
the pathophysiological and clinical aspects that are
associated with EVA. Previous research has for dec-
ades described and investigated atherosclerosis, a pro-
cess that starts in the intima layer of the arterial wall
and becomes proximal to many cardiovascular events
caused by athero-thrombotic disease. As the core com-
ponent of EVA is arterial stiffness, arteriosclerosis,
which is mainly influenced by morphological changes
in the arterial media layer, but also in other layers, we
have focused on different characteristics and mechan-
isms associated with stiffness of the large elastic arter-
ies. We also consider EVA based on an integrated
view linking the macro- with the microcirculation.
This is because hemodynamic forces influenced by
stiffness may also cause harm to the peripheral smaller
vessels due to the increased pulsatile energy that is
transmitted, for example, in the brain. Another aspect
of a more integrated approach identifies important
contributing factors for EVA also from the intima
(endothelial dysfunction) and the adventitia (impaired
function of vasa vasorum and innervation, accompanied
by increased secretion of cytokines from the perivascu-
lar adipose tissue causing local inflammation) when
impaired glucose metabolism could further contribute
to stiffening by glycosylation. Therefore, we consider
EVA to be a fruitful scientific concept to promote
research on early changes of the arterial wall, pro-
grammed already in utero and early life and influenced
by genetic and environmental factors. As meta-
analyses have documented that arterial stiffness
(increased aortic pulse wave velocity, aPWV) is an
independent risk marker for future cardiovascular risk
and total mortality, adjusted for conventional risk fac-
tors, we consider it of importance to find new ways to
find, diagnose, and treat subjects with signs of EVA.
Still however, neither an exact definition nor a targeted
treatment exists for EVA, but several attempts are
being made to find such alternatives. We therefore
invite the reader to contribute to the lively discussion
on EVA with data from different populations and eth-
nic groups, as well as with data from basic and clinical
science. This could contribute to early detection of at-
risk individuals, for example, from at-risk families
with early onset cardiometabolic disease, for preven-
tion based on improved life style as well as drug ther-
apy when needed. This is not to deny the importance
of atherosclerosis and the evidence-based methods that
exist to prevent cardiovascular events by control of
hypertension and hyperlipidemia as well as smoking
cessation, but we consider that EVA is a feature start-
ing early in life and that later in life components of
arteriosclerosis and atherosclerosis will be intertwined
in further promoting cardiovascular disease risk.
In an historical perspective, the interest in arterial
function and stiffness contributing to hemodynamic
changes predates the clinical measurement of blood
pressure and diagnosis of hypertension as we know it.
In London, the physician Fredrik Akbar Mahomed car-
ried out studies on pulse wave properties in arteria
radialis with his own sphygmograph and published in
1877:
It is very common to meet with people apparently in good
health who have no albumen in the urine, who constantly
present a condition of high arterial tension when examined by
the aid of the sphygmograph. [1]
We therefore date the interest in large arteries and
stiffness to an era before clinical hypertension was rec-
ognized [2], and thus the EVA concept [3 5] attempts
to bridge more than a century to revive the importance
of large arteries and their properties in cardiovascular
medicine.
Peter M. Nilsson
Malmö, Sweden
Michael H. Olsen
Odense, Denmark
Stéphane Laurent
Paris, France
xi](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-12-2048.jpg)
![References
[1] Mahomed FA. Remarks on arterio-capillary fibrosis and its clini-
cal recognition. Lancet 1877;110(2816):232 4.
[2] Riva-Rocci S. Un nuovo sfigmomanometro. Gazz Med Torino
1896;50 51:1001 7.
[3] Nilsson PM, Lurbe E, Laurent S. The early life origin of vascular
ageing and cardiovascular risk. J Hypertens 2008;26:1049 57.
[4] Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: a tale of
EVA and ADAM in cardiovascular risk assessment and preven-
tion. Hypertension 2009;54:3 10.
[5] Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K,
Parati G, et al. Early vascular ageing in translation: from labora-
tory investigations to clinical applications in cardiovascular pre-
vention. J Hypertens 2013;31:1517 26.
Frederick H. H. Akbar Mahomed (c. 1849 1884), arterial studies Scipione Riva-Rocci (1863 1937), measurement of systolic blood
pressure
xii PREFACE](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-13-2048.jpg)
![C H A P T E R
1
Historical Aspects and Biology of Aging
Peter M. Nilsson
Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Aging is a universal finding in humans, afflicting biological processes as well as maturation and deterioration
of organ function. There exist a number of theories on how aging is programmed and develops as presented in
gerontology, the science of normal aging. Not only the “wear and tear” hypothesis exists but also aging models
dependent on the influence of oxidative stress, metabolic processes, and the accumulation of genetic damage on
the DNA and impaired genetic repair functions [1]. Modern discoveries point to the role of longevity-regulating
genes, so-called “gerontogenes” [2]. These gerontogenes are classified as lifespan regulators, mediators, effectors,
housekeeping genes, genes involved in mitochondrial function linked to metabolism, and genes regulating
cellular senescence and programmed cell death (apoptosis) [2]. Intensive research is directed to understand what
regulates aging and how to control this, not at least apoptosis, of vital importance to understand organ develop-
ment and changes in health and disease. The maximum lifespan recorded was 122 years for a French woman
(Jean Calment, France, 1875 1977).
Even if it is very hard to disentangle the different influences on the aging process and to judge upon the
accuracy of the different hypotheses to explain human aging in general, it comes natural to view aging in its
evolutionary context as all aspects of human biology, and even cognitive function, are supposed to be influenced
by evolutionary selection mechanisms during millennia perspectives.
EVOLUTIONARY TRAITS, GENES, AND THE ENVIRONMENT INFLUENCING AGING
From an evolutionary perspective the lifespan of mammals has been formed by selective processes based
on genetic regulation of survival and reproduction in relation to available nutrition, environmental hazards,
and competition for resources. According to the “disposable soma hypothesis” by Kirkwood [3] there exists
a trade-off between maintenance of bodily functions, depending on energy investments, and the costs of
reproduction, especially for women. This is why, according to this hypothesis, women with a higher number
of offspring will be at increased risk for a shorter lifespan as compared to women with fewer offspring, if basal
health and social conditions tend to be equal, as studied in British noble families over many centuries [4]. This
is also influenced by nutritional resources, as reproductive capacity in women tends to cease during periods of
famine and starvation.
Behind such traits there must be genetic regulators, as evolution works via genetic adaption and fitness in
relation to a changing environment. A further support for the genetic influence on longevity is the family resem-
blance of longevity as well as risk of some chronic disease conditions that tend to run in families, that is, clusters
of cardiovascular disease [5] and metabolic abnormalities. According to a number of studies the genetic explana-
tion of longevity is approximately 25% [6]. This leaves a substantial proportion of longevity to the influence of
environmental factors or to epigenetic mechanisms (gene environmental interactions). It is still unclear if true
life-prolonging genes exist in humans as in other less-developed organisms (Caenorhabditis elegans), or if a long
lifespan is a marker of the less strong impact or lack of disease-related genes in some individuals. According to
1
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![environmental factors, there are many such detrimental factors well known to decrease lifespan, for example,
smoking, infectious disease, and malnutrition, but the only environmental factor known to prolong life in
mammals, at least in rodents and monkeys, is continuous calorie restriction [7]. This is believed to exert similar
effects in humans but still not proven. Nevertheless some individuals have adopted a lifestyle based on calorie
restriction and balanced physical activity, hoping for a prolonged life.
CHANGES DURING THE TWENTIETH CENTURY IN LIFE EXPECTANCY
There is no doubt that the rapid increase in longevity during the past twentieth century is an indication
of the strong influence of environmental factors on human lifespan, reflecting better nutrition and housing,
improved hygiene and conditions in early life, as well as the progress of healthcare and improved medical
treatment, even if temporary setbacks have also been noticed, for example, in Russia during the 1990s [8].
The negative socioeconomic changes for many citizens in Russia during this period could be one compo-
nent of the increased cardiovascular risk based on gene environmental interactions in high-risk popula-
tions [9]. On the other hand, it is still necessary to understand the biology (and genetics) behind the aging
process, as there are still many examples of differential aging also in developed countries. A proof of the
role of genetic influences on aging and shortened lifespan are the rare conditions of Hutchinson Gilford
progeria in children and Werner’s syndrome in middle-aged subjects [10]. Even if these rare conditions are
not possible to causally treat today, they represent an opportunity to learn more about biological changes
taking place during the aging process, especially when it is upregulated in the progeria syndromes with
shortened lifespan.
EARLY LIFE PROGRAMMING EFFECTS
Human life starts at the conception followed by a growth during 9 months in fetal life in utero when organs
are formed and developed based on numerous cell divisions under genetic regulation. Nutritional factors are of
great importance for this process, as mediated by the feto-placental unit and influenced by maternal dietary
intakes. For more than 30 years now, researchers have documented the importance of fetal growth and birth
weight for bodily development and health also in adult life. Starting with early observations from northern
Norway by Forsdahl [11] and by Gennser [12] in Sweden, David Barker and many other colleagues developed a
concept based on the detrimental health consequences of fetal growth retardation leading to the small-for-
gestational age (SGA) phenotype in newborn babies. This condition in early life was associated with increased
levels of cardiovascular risk factors (hypertension, dyslipidemia, and hyperglycemia) and even overt type 2
diabetes in adult life, but also with impaired neurocognitive developments and a number of other adverse health
conditions, summarized in the so-called “Barker hypothesis” [13]. In more recent years a new paradigm has
evolved with a focus not only on fetal growth and birth weight as outcomes but also on postnatal growth
patterns. Of special importance for adult health is the combination of impaired fetal growth, causing SGA at
birth, combined with a rapid catch-up growth pattern in the first few years of life. This has been named the
“mismatch” growth pattern when different organs are programmed in utero for a life with scarce resources and
calorie depletion but later on the newborn child will experience the opposite, an environment with a surplus of
calories and nutritional abundance. This may negatively impact on organ development and increase the risk
of cardiometabolic disturbances in adult life. The most well-known protagonists of the “mismatch” hypothesis
today are Peter Gluckman and Mark Hanson, with important reviews on the topic [14]. They are both active
in the “Developmental Origins of Health and Disease” (DOHaD) society, to further explore the mismatch
hypothesis.
An even more recent hypothesis of early life programming of adult disease risk is linked to the impact on
child gut microbiota from the mother during delivery [15], as a detrimental gut microbiota pattern could be one
factor increasing the risk of obesity in adult life and adverse health conditions such as cardiovascular disease [16]
and type 2 diabetes [17]. It is believed that the mother’s gut bacteria will normally colonize the gastrointestinal
system of the newborn child and that this will protect from overgrowth of more deleterious skin bacteria that
could be associated with later disease risk [15].
2 1. HISTORICAL ASPECTS AND BIOLOGY OF AGING
EARLY VASCULAR AGING (EVA)](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-15-2048.jpg)
![It is likely that such influences in early life from nutrition, growth patterns, and microbiota patterning
could also impact on aging in general and/or age-related medical conditions. These include not only defined
chronic disease but also the increasing frailty, that is, related to sarcopenia and osteoporosis in old age, as
well as cognitive decline [18]. Newer studies on the life of centenarians have also highlighted the role of
early life influences, for example, the longevity associated with being born to younger mothers (first-born)
when siblings within the same family are compared [19]. There also seem to exist large gender differences
found in longevity determinants for males and females, suggesting a higher importance of occupation
history for male centenarians as well as a higher importance of home environment history for female
centenarians [19].
VASCULAR AGING IN PERSPECTIVE
What implications do these observations have for the concept of early vascular aging (EVA) with
increased arterial stiffness as a central characteristic [20]? First of all, EVA is likely to be an expression of
biological aging in general and some of the mechanisms regulating aging in other organs must also be appli-
cable to the vascular tissue, especially in the arterial wall. This is believed to be possible to estimate by
measuring leukocyte telomere length (LTL), a proposed marker of biological aging as LTL tends to shorten
with every cell division. However, in a large population-based study, the Asklepios study in Belgium, no
association between pulse wave velocity (PWV), a marker of arterial stiffness as the core characteristic of
EVA, and LTL was seen in a cross-sectional analysis [21]. On the other hand, some associations were seen
with cardiac function, which is why the authors concluded that in a generally healthy, young to middle-
aged population, LTL is not related to left ventricular (LV) mass or systolic function, but might be associated
with an altered LV filling pattern, especially in women. The Asklepios study purposefully selected healthy
individuals for screening.
The findings of this large and more recent Belgian study contradicts earlier observations from a smaller
French study [22], when it was concluded that LTL provides an additional account to chronological age with
regard to variations in both pulse pressure and PWV among men, such that men with shorter telomere length
are more likely to exhibit high pulse pressure and PWV, which both are indices of large artery stiffness
(arteriosclerosis). The longer telomere length in women of that study suggests that for a given chronological
age, biological aging of men is more advanced than that of women [22].
How to resolve these contradictory findings? It is believed that cross-sectional analyses of LTL in relation to
organ function is probably not enough. Of even greater importance could be to evaluate relationship with telo-
mere attrition rate based on repeated measurements of LTL over a time period. Few studies have applied this
more laborious and costly method, and this is why more studies are needed with precise methods for measuring
LTL and also attrition rate over time [23]. Before such data are available it is hard to judge on the true relation-
ship between LTL and telomere biology, as a marker of aging, and arterial stiffness representing vascular aging.
On the other hand, there are numerous studies to show associations between shorter telomeres and vascular
disease based on atherosclerosis, as recently summarized [24].
NEW MODELS AND INTERVENTIONS TO INFLUENCE AGING
If a deeper understanding can be achieved of the aging process in general, with its vascular implications, this
could also lead to the establishment of new experimental models to test the reversibility (if any) of these pro-
cesses. Molecules that suppress these age-related changes would provide an excellent medical intervention target
for vascular disorders. Mammalian Sir2 (SIRT1, a NAD1
-dependent deacetylase), previously shown to extend the
lifespan of lower organisms, is a promising target molecule to influence some aspects of vascular aging. The
influence of SIRT1 in various pathophysiological processes of vascular aging has been summarized and Wang
et al. proposed that SIRT1 and its activators can become novel therapeutic targets for age-related vascular disease
[25]. Time will tell if this intervention model will be able to shed new light on the aging process in general and
vascular aging in particular (Table 1.1).
3
NEW MODELS AND INTERVENTIONS TO INFLUENCE AGING
EARLY VASCULAR AGING (EVA)](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-16-2048.jpg)
![Acknowledgment
This review was supported by a grant from the Research Council of Sweden for studies on early vascular aging in the population.
References
[1] Kolovou GD, Kolovou V, Mavrogeni S. We are ageing. Biomed Res Int 2014;2014:808307.
[2] Moskalev AA, Aliper AM, Smit-McBride Z, Buzdin A, Zhavoronkov A. Genetics and epigenetics of aging and longevity. Cell Cycle
2014;13:1063 77.
[3] Kirkwood TB, Rose MR. Evolution of senescence: late survival sacrificed for reproduction. Philos Trans R Soc Lond B Biol Sci
1991;332:15 24.
[4] Westendorp RG, Kirkwood TB. Human longevity at the cost of reproductive success. Nature 1998;396:743 6.
[5] Nilsson PM, Nilsson JA, Berglund G. Family burden of cardiovascular mortality: risk implications for offspring in a national register
linkage study based upon the Malmö Preventive Project. J Intern Med 2004;255:229 35.
[6] Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet 2013;132:1323 38.
[7] Smith Jr DL, Nagy TR, Allison DB. Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest
2010;40:440 50.
[8] Plavinski SL, Plavinskaya SI, Klimov AN. Social factors and increase in mortality in Russia in the 1990s: prospective cohort study. BMJ
2003;326:1240 2.
[9] Nilsson PM. Genetic and environmental determinants of early vascular ageing (EVA). Curr Vasc Pharmacol 2012;10:700 1.
[10] Ding SL, Shen CY. Model of human aging: recent findings on Werner’s and Hutchinson Gilford progeria syndromes. Clin Interv Aging
2008;3:431 44.
[11] Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev
Soc Med 1977;31:91 5.
[12] Gennser G, Rymark P, Isberg PE. Low birth weight and risk of high blood pressure in adulthood. Br Med J (Clin Res Ed)
1988;296:1498 500.
[13] Cooper C, Phillips D, Osmond C, Fall C, Eriksson J. David James Purslove Barker: clinician, scientist and father of the “fetal origins
hypothesis”. J Dev Orig Health Dis 2014;5:161 3.
[14] Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl
J Med 2008;359:61 73.
[15] Reinhardt C, Reigstad CS, Bäckhed F. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr
2009;48:249 56.
[16] Ettinger R, MacDonald K, Reid G, Burton JP. The influence of the human microbiome and probiotics on cardiovascular health. Gut
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[17] Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut 2014;63:1513 21.
[18] Langie SA, Lara J, Mathers JC. Early determinants of the ageing trajectory. Best Pract Res Clin Endocrinol Metab 2012;26:613 26.
[19] Gavrilov LA, Gavrilova NS. New developments in the biodemography of aging and longevity. Gerontology 2014; Dec 20. [Epub ahead
of print] PubMed PMID: ,25531147..
[20] Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K, Parati G, et al. Early vascular ageing in translation: from laboratory investi-
gations to clinical applications in cardiovascular prevention. J Hypertens 2013;31:1517 26.
TABLE 1.1 Some Factors of Importance to the Shaping of Human Aging and Longevity
Genetic programming, based on evolutionary selection
Epigenetic influences (gene environmental interaction and imprinting)
Early life programming (nutrition, growth rates, neurocognitive function)
Family patterns (sibling rank, age of parents, shared microbiota)
Adult lifestyle (smoking, nutrition, physical activity)
Telomere biology
Health problems and disease
Medical treatment and interventions
Societal factors and social support
Secular trends
4 1. HISTORICAL ASPECTS AND BIOLOGY OF AGING
EARLY VASCULAR AGING (EVA)](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-17-2048.jpg)
![[21] Denil SL, Rietzschel ER, De Buyzere ML, Van Daele CM, Segers P, De Bacquer D, et al. Asklepios investigators on cross-sectional
associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study. PLoS One 2014;
9(12):e115071.
[22] Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J, et al. Telomere length as an indicator of biological aging: the gender
effect and relation with pulse pressure and pulse wave velocity. Hypertension 2001;37(2 Pt 2):381 5.
[23] Nilsson PM. Mediterranean diet and telomere length. BMJ 2014;349:g6843 ,http://dx.doi.org/10.1136/bmj.g6843.. PubMed
PMID: ,25467755..
[24] Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg
2010;40:17 26.
[25] Wang F, Chen HZ, Lv X, Liu DP. SIRT1 as a novel potential treatment target for vascular aging and age-related vascular diseases. Curr
Mol Med 2013;13:155 64.
EARLY VASCULAR AGING (EVA)
5
REFERENCES](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-18-2048.jpg)
![C H A P T E R
2
Cellular and Molecular Determinants
of Arterial Aging
Patrick Lacolleya
, Pascal Challandeb
, Veronique Regnaulta
,
Edward G. Lakattac
and Mingyi Wangd
a
Institut National de la Santé et de la Recherche Médicale—INSERM U1116; Université de Lorraine, Nancy, France;
b
Université Pierre et Marie Curie, CNRS—UMR 7190, Paris, France; c
Laboratory of Cardiovascular Science,
Intramural Research Program, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD, USA;
d
Laboratory of Cardiovascular Sciences Biomedical Research Center,
Baltimore, MD, USA
INTRODUCTION
The aging of the world population has progressed unabated as more adults are surviving into their senior
years. The heterogeneity of aging phenotypes results from genetic and epigenetic impacts on different cell
types and tissues throughout a lifetime [1]. Importantly, arterial aging is intertwined with hypertension and
atherosclerosis at the molecular, cellular, vascular, and clinical levels because the aged arterial wall is fertile
soil for their pathogenesis. Age-associated arterial diseases account for a large part of total mortality,
approximately 29% of all deaths. Hypertension is a major factor to promote arterial aging. The prevalence of
hypertension is around 50% and 60% over 60 and 70 years of age, respectively [2]. It is higher in men than in
women before 50 years of age, whereas in older persons, the sex difference in prevalence of hypertension is
greater in women than in men [3]. The prevalence of hypertension is similar in various regions of the world
[4], whereas the prevalence of stroke is 3.5-fold higher in low-income than in middle- and high-income
countries [5].
Arteriosclerosis is defined as an age-associated stiffening and dilatation of the large arteries. Atherosclerosis
represents the leading cause of mortality and is characterized by four major steps: (i) an initial endothelial activa-
tion by hemodynamic factors and dyslipidemia followed by leucocyte transmigration and activation involving
cytokines and innate or adaptive immunity; (ii) a promotion step, which includes development of foam cells and
lipoprotein retention; (iii) a progression step by growth of complex plaques; and (iv) plaque destabilization and
thrombosis. Atherosclerosis within the arterial wall leads to inflammation, accumulation of fibronectin, collagen
deposition, and fibrosis.
Aging is characterized by chronically elevated levels of low-grade circulating inflammatory molecules such as
monocyte chemoattractant protein-1 (MCP-1) [6]. In particular, the interactions of environmental, systemic, and
local chronic stress signals are conferred to vascular cells and the matrix, which insidiously facilitate arterial
adverse remodeling through proinflammatory signaling such as the angiotensin II (Ang II) signaling cascade
with aging. This process leads to endothelial disruption, thrombosis, senescence, glycoxidation, fibrosis, elastin
fragmentation, calcification, and amyloidosis [1,7 9]. Importantly, this proinflammatory response accelerates the
cardiovascular burden of both hypertension and atherosclerosis in the elderly [7,9]. This review focuses upon the
key molecules involved in inflammatory mechanisms and pathways that are implicated in the aging of the arte-
rial wall (Figure 2.1).
7
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![CYTOSKELETAL AND CONTRACTILE PROTEINS IN THE AGING ARTERIAL WALL
Cytoskeletal Proteins
Desmin and vimentin are the main components of intermediate filaments implicated in mechanotransduc-
tion (Figure 2.1). Both desmin and vimentin are generally found to be decreased with advancing age in rat
smooth muscle cells (SMCs) [10 13]. The mechanical properties of SMCs through cytoskeletal proteins contrib-
ute to the increased stiffness of the aorta in old versus young monkeys [14]. Desmin is required in the dilatory
and contractile functions of SMCs and provides an efficacious interaction between the cytoskeletal and the con-
tractile elements to maintain the mechanical integrity of SMCs. In old SMCs there is a shift toward small
vimentin fragments, and co-localization with calpain-1 argues for calcium-dependent vimentin cleavage by
calpain-1 [15].
Contractile Proteins
Smooth muscle (SM) myosin heavy-chain content/isoform expression is the most discriminant marker of
fully differentiated SMCs (Figure 2.1). Alteration in SM myosin has been reported in aged rats. In SMCs cul-
tured from 30-month-old Fischer 344XNB rats or 24-month-old Wistar rats, SM myosin is decreased compared
to SMCs isolated from 6-month-old rats [12,13,16]. SMCs freshly isolated from 18-month-old Wistar rat aortae
showed percentages of SM-myosin-positive cells similar to those observed in newborn and young adult rat
SMCs [10]. Higher tissue content of myosin heavy chain and a higher ratio of SM1/SM2 isoforms have been
reported in aortae of 36-month-old Fischer 344/NNiaHSd X Brown Norway/BiNia compared to those of
6-month-old rats [17]. Interestingly, embryonic myosin in SMCs is increased in aged thickened intima in
humans [18]. In addition, the contractile regulatory light-chain MyL9 is overexpressed in endothelial layers of
aging rats and is associated with an increase of endothelial cell (EC) contraction resulting in endothelial
hyperpermeability [19].
Cellular and molecular determinants of arterial aging
RAAS
ROS/RNS
NO
MCP-1
MMPs
MFG-E8
Adhesion molecules
Contractile proteins
Cytoskeletal proteins
CArG Box
NF-κB
Ets-1
SIRT1
FoxO3
Autocrine/paracrine
/Juxtacrine
proinflammatory
Shift
Intima media thickness (IMT)
Fibrosis
Elastin fragmentation
Calcification
Glycoxidation
Stiffening
Aging:
Stiffening↑
Systolic blood
pressure
(SBP)↑
Endothelial
Dysfunction
Signaling loop Cellular
phenotype
Vascular
phenotype
Vascular
function
Clinical
phenotype
FIGURE 2.1 Diagram of cellular and molecular determinants of arterial aging.
8 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING
EARLY VASCULAR AGING (EVA)](https://image.slidesharecdn.com/95373-250416222954-22998f14/75/Early-vascular-aging-EVA-new-directions-in-cardiovascular-protection-1st-Edition-Laurent-20-2048.jpg)
![CELLULAR MATRIX STRUCTURE IN THE AGING ARTERIAL WALL
It is known that the elastin/collagen ratio plays an important role in arterial mechanical properties [20].
Changes in both content and organization of elastin and collagen fibers influence the arterial wall with age. When
expressed as a percentage, elastin percentage is decreased while collagen percentage is increased, which causes a
net decrease in the elastin/collagen ratio with aging [20]. The bulk of the elastin is highly susceptible to age-related
changes, which involve an increase in associated polar amino acids, the binding and accumulation of calcium and
lipids, and fragmentation due to enzymatic degradation or fatigue processes [20,21]. Advanced glycation end-
products (AGEs)-mediated cross-linking of elastin increases with age in the human aorta [22]. By contrast, collagen
fibrils become organized into multibranched bundles and stiffen [23].
PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR
EVENTS IN THE AGING ARTERIAL WALL
The Renin Angiotensin Aldosterone System
The components of the renin angiotensin aldosterone system (RAAS) are important aspects of the proinflam-
matory system (Figure 2.1), including angiotensin converting enzyme (ACE), Ang II, and its receptor AT1. The
transcription, translation, and activity of ACE markedly increase within both ECs and vascular SMCs (VSMCs) in
the arterial wall with aging in rodents, nonhuman primates, and humans [18,24,25]. In addition, an alternative
angiotensin convertase, chymase, increases within the arterial wall with aging [25]. As a result, the cleaved prod-
uct, Ang II protein, becomes markedly increased, particularly in the thickened intima of rats, nonhuman primates,
and humans [15,18,25 27]. Furthermore, the Ang II receptor, AT1, is up-regulated within the old arterial wall [18].
Ang II stimulates aldosterone secretion. The mineralocorticoid receptor (MR) expression is increased in the
arterial wall with aging [28,29]. Furthermore, aging increases the sensitivity of MR to Aldo. Increased MR activity
in aged rats promotes a proinflammatory phenotype via an extracellular signal-regulated kinase 1/2/mitogen-
activated protein kinase/epidermal growth factor receptor (ERK-1/2/MAPK/EGFR)-dependent pathway, con-
tributing to the synthetic phenotypic shift of SMCs within the aging arterial wall [28]. In addition, aldosterone
mediates an increase in the expression of EGFR in SMCs with aging, further reinforcing its proinflammatory
effects [28]. Notably, cardiotrophin-1 (CT-1), a proinflammatory cytokine overexpressed in SMCs by aldosterone
[30], also contributes to vascular aging because CT-1 treatment increases SMC proliferation and collagen produc-
tion, whereas its invalidation increases longevity in mice [31].
Increased activation of the RAAS and an increase in oxidative stress that contributes to arterial proinflammation
are both implicated in age-related arterial remodeling. Chronic infusion of a physiologically relevant dose of Ang II
to adult rats (8-months-old) increases expression of molecules that comprise the proinflammatory profile, that is,
matrix metalloproteinase type II (MMP-2), MCP-1, calpain-1, transforming growth factor-β1 (TGF-β1), and nicotin-
amide adenine dinucleotide phosphate (NADPH) oxidase. The infusion also elicits the age-associated increase in
aortic and coronary structural manifestations, that is, intimal and media thickening of old (30-month-old),
untreated arteries [27]. In addition, the α-adrenergic receptor agonist, phenylephrine, increases arterial Ang II pro-
tein, causing MMP-2 activation and intimal and medial thickening [27]. In contrast, chronic ACE inhibition and
AT1 receptor blockade, beginning at an early age, markedly inhibit the expression of proinflammatory molecules
and delay the progression of age-associated aortic remodeling [24,32]. Interestingly, long-term AT1 blockade
improves endothelial function, decreases blood pressure, and doubles the life span of hypertensive rats similar to
normotensive animals [33]. Disruption of the AT1 receptor retards arterial inflammation, promotes longevity, and
improves survival after myocardial infarction in mice [34].
Proteinases
Matrix Metalloproteinases
An important component of age-associated vascular remodeling is degradation and resynthesis of extracellular
matrix (ECM) (Figure 2.1). Specialized enzymes known as matrix metalloproteinases (MMPs) mediate the degra-
dation process. Among MMPs, the MMP-2 mRNA and protein increase in the aortic walls of aged rodents, non-
human primates, and humans and is also activated by Ang II signaling [25,27,35 38]. The increased MMP-2
activity is mainly seen within the thickened intima and the inner media in rodents and monkeys [25,39]. The
9
PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR EVENTS IN THE AGING ARTERIAL WALL
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![enhanced MMP-2/-9 activity is also observed in the aortae from human autopsy in the “grossly normal vessels”
with aging [18]. An increase of MMP-2/-9 activity is attributable to not only an enhanced transcription and trans-
lation, but also to an imbalance of its activators, membrane-type-1 matrix metalloproteinase (MT1-MMP), urine
plasminogen activator, and tissue plasminogen activator and inhibitors, tissue inhibitor of MMP-2 (TIMP-2), and
plasminogen activator inhibitor [25,39].
Notably, the micro-processing of extracellular bioactive molecules via MMP activation likely facilitates the ini-
tiation and progression of hypertension. Activated MMP-2 increases the bioavailability of vasoconstrictors such
as big endothelin-1 (ET-1), while decreasing the vasodilator such as adventitial calcitonin gene-related peptide
(CGRP) and endothelial NO-synthase enzyme (eNOS) [7,40,41]. MMP-2-7/-9 reduces the density of the extracel-
lular domain of β(2)-adrenergic receptor in blood vessels and enhances the arteriolar tone [42,43].
Interestingly, age-associated arterial remodeling due to arterial wall collagen deposition and elastin fragmenta-
tion known as elastolysis is associated with an increase in arterial MMP activation. Chronic administration of a
broad-spectrum MMP inhibitor markedly blunts the age-associated increases in aortic gelatinase and interstitial
collagenase activity and reduces the elastin network degeneration, collagen deposition, MCP-1 expression, TGF-
β1 activation, and Smad-2/-3 phosphorylation [44]. Importantly, MMP inhibition also substantially diminishes
pro-ET-1 activation and down-regulates Ets-1 expression [44].
Calpain-1
Calpain-1 is a calcium-dependent intracellular proteinase and is an important activator of MMP-2 [45].
Transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage
aortic SMCs from old rats compared to young animals [15]. Co-localized calpain-1 and Ang II are within the
aged arterial wall [15]. Ang II induces calpain-1 expression in the aortic walls in vivo and aortic rings ex vivo and
SMCs in vitro [15]. Over-expression of calpain-1 in young SMCs leads to cleavage of intact vimentin, an increase
of migratory capacity, and calcification mimicking that of old SMCs [15].
In addition, communication between MMP-2 and calpain-1 is observed in aged arterial walls or SMCs. Aging
induces both MMP-2 and calpain-1 expression and activation in the arterial wall [45]. Co-localization of calpain-1
and MMP-2 are observed within old rat SMCs [45]. Over-expression of calpain-1 induces MMP-2 transcription,
translation, and activity, in part, due to increasing the ratio of MT1-MMPs to TIMP-2 [45]. These effects of
calpain-1 over-expression-induced MMP-2 activation are linked to increased TGFβ-1/Smad-2/-3 signaling, and
collagen I, II, and III production [38,45]. Cross-talk of two proteases, calpain-1 and MMP-2, synergistically modu-
lates ECM remodeling and facilitates calcification by enhancing collagen production in SMCs with aging [45]. A
switch from a de-differentiated to a pro-calcificatory phenotype of SMCs also induces vascular calcification with
advancing age [46].
Transforming Growth Factor-β1
Arterial TGF-β1 mRNA and protein are abundantly present in the aged arterial wall (Figure 2.1) [27,38].
Co-expression of both TGF-β1 and TGF-β1 receptor II (TβIIR) proteins increases in rat aortae at 30 versus 8 months
of age [38]. TGF-β1 plays an important role in arterial fibrosis [27,29,37,38]. TGF-β1 expression is tempo-spatially
associated with the collagen expression and local fibrosis in the aging arterial wall [27,39]. In vitro studies show
that ECs and VSMCs treated with TGF-β1 increase collagen types I and III mRNA, and this is attenuated by a
TβIIR blocker [47,48]. Importantly, enhanced expression of active TGF-β1 and collagen deposition in the thick-
ened vascular wall of aged rats is, in part, produced by exaggerated MMP-2 activation of latent transforming
protein-1 [38]. Furthermore, the increased MCP-1 co-localizes with TGF-β1, which suggests an interaction may
exist between MCP-1 production and TGF-β1 activity [37]. Indeed, TGF-β1 transcription, translation, and activity
increase in VSMCs treated in response to MCP-1 and enhance production of ECM [37].
Monocyte Chemoattractant Protein-1
MCP-1, a downstream molecule of Ang II signaling, is a potent inflammatory cytokine (Figure 2.1). With
aging, MCP-1 mRNA increases within aortic walls in FXBN rats [49]. The increased MCP-1 protein is predomi-
nantly localized to the thickened intima [49]. The increased MCP-1 also co-localizes with TGF-β1, suggesting an
interaction between MCP-1 production and TGF-β1 activity [37]. Indeed, TGF-β1 transcription and translation
increase in SMCs treated with MCP-1 and exposure of SMCs to MCP-1 increases TGF-β1 activity [37]. Thus,
10 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING
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![MCP-1 signaling also initiates the fibrosis of aging. Notably, MCP-1 dimerization is necessary for chemoattractant
activity [50]. MCP-1 forms dimers at local high concentrations such as in the aged arterial wall, which is likely to
strongly attract the invasion of SMCs [26].
Reactive Oxygen Species and NO Bioavailability
Non-phagocytic NAD(P)H oxidase, which generates arterial cell reactive oxygen species (ROS) in the vascular
system, is activated by Ang II signaling (Figure 2.1). NAD(P)H oxidase membrane-bound components p22phox
and gp91phox are increased in the endothelium of aortae from old versus young rats [51]. Further, cytosolic com-
ponent p47phox also increases in the arterial wall with aging in rodents [52,53]. Importantly, anti-oxidant Cu/Zn
superoxide dismutase (SOD1), Mg SOD (SOD2), and ECM superoxide dismutase (ECM-SOD/SOD3) decrease in
the arterial wall, which accompanies aging in rats [54 57]. Indeed, with aging, a loss of balance between oxidase
and dismutase has been observed in the coronary arterial wall and aortic wall of rats, consequently resulting in
an increase of superoxide and hydrogen superoxides [58 61].
Nitric oxide (NO) is a diffusible gas that can act as an intracellular and intercellular messenger in the arterial
wall that is avidly scavenged by superoxide anions. The main source of NO is the ECs in the arterial wall.
Endothelial production of NO becomes reduced with advancing age [55,62,63]. NO is generated from the meta-
bolic conversion of L-arginine into L-citrulline by the activity of the NOS. Two major classes of NOSs have been
described in the vascular system. One isoform is constitutively expressed (eNOS) under basal conditions and is
involved in the endothelium-dependent vasodilation response. Another isoform, iNOS, is inducible by inflamma-
tion [64]. While iNOS is absent in the aortic segments of young rats, a marked expression of the iNOS protein is
observed in segments of aging rats [64]. The expression of both eNOS and iNOS is altered in the arterial wall
with aging [55,64,65].
Augmented release of ROS subsequently inactivates NO with increasing age [61]. Reactive nitrogen species are
also important modulators of NO bioavailability [66]. The interaction of NO and free radicals will result in subse-
quent formation of peroxynitrite (ONOO ). Strong experimental evidence has recently been presented for a close
association between the formation of ONOO and age-associated vascular endothelial dysfunction [66].
The aging arterial wall is a frequent target of modifications by reactive oxidative compounds such as NADPH
oxidase and reducing sugars known as glycoxidation [8,67 70]. AGEs are easily formed by a reaction between
sugar chains and biologic amines of oxidized collagen. Stabilized glycated proteins accumulate over a lifetime
and contribute to age-associated multiple structural and physiologic changes in the vascular system such as
increased vascular stiffness, endothelial dysfunction, and inflammation [8].
MFG-E8, Fibronectin, and Integrin Receptors
MFG-E8 and Its Fragment Medin
A high-throughput proteomic screening identified milk fat globule-EGF-8 (MFG-E8) (Figure 2.1), a cell adhe-
sion protein, as an important Ang II signaling signature of aging arterial walls [26]. Levels of arterial MFG-E8
and its degradation fragment, medin, both increase and accumulate in the aorta with aging in rodents, nonhu-
man primates, and humans [26,71,72]. MFG-E8 is induced by Ang II and itself induces the expression of MCP-1
in SMCs within the aortic wall of old rats [26].
Integrins comprise a widely distributed family of cell surface α/β heterodimeric adhesion receptors that bind
cells to components of the ECM such as fibronectin. They act as sensing and signaling transmembrane receptors.
Integrin α5β1 and αvβ3/5 expressions are increased in the arterial wall of old hypertensive rats, contributing to
arterial stiffening [73,74]. Co-expression and increased physical interaction of MFG-E8 and integrin αvβ5 occur
with aging in both the rat aortic wall in vivo and in SMC in vitro, promoting SMC invasion and proliferation with
aging [26,75].
Increased amyloid deposition is a characteristic of the aged arterial wall. A specific amyloid protein, known as
medin, is deposited in the aortic media in the majority of Caucasians over 50 years of age. In addition, both med-
in and MFG-E8, in an amyloid protein complex, bind to tropoelastin [76 78]. Thus, MFG-E8/medin amyloid
may likely be a factor in the increased aortic stiffness that accompanies advancing age. Indeed, serum MFG-E8
levels and pulse wave velocity, an index of arterial stiffening, correlate with cardiovascular risk factors in old
humans with type 2 diabetes [79].
11
PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR EVENTS IN THE AGING ARTERIAL WALL
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![Fibronectin
In large arteries, the increase in α5β1 and fibronectin participates in the adaptation to mechanical stress in aged
spontaneously hypertensive rats through increased numbers of cell matrix attachments and phenotypic changes
[80]. Pressure and age induce accumulation of fibronectin and more specifically the EIIIA isoform [21].
Paralleling the increase in integrins in the aging vasculature are marked increases in fibronectin levels [73].
Inhibition of αvβ3 integrin increases senescence of SMCs [81], which suggests an up-regulation of this integrin
with aging. Interestingly, the level of integrin β4 increases in the endothelium of mouse aorta with aging, which
contributes to vascular EC senescence by affecting the levels of p53 and ROS [82].
TRANSCRIPTION FACTORS
Cytoskeletal Serum Response Transcription Factor
Serum response factor (SRF) (Figure 2.1) is a MADS (MCM1, Agamous, Deficiens, SRF) box transcription factor
that regulates numerous cytoskeletal SMC genes, which produce SM-actin, SM-myosin heavy chain, calponin,
troponin, dystrophin, and desmin through specific CArG-element-binding sites. SRF has also been implicated in
EC migration during sprouting angiogenesis [83]. SRF is highly expressed in SMCs compared to most other tis-
sues and appears to increase with aging (personal data) and in cerebral arteries of Alzheimer’s patients [84]. The
development of hypertension in spontaneously hypertensive rats is also linked to an increased SRF-binding affin-
ity to the CArG box present in the SM-myosin light-chain kinase promoter, resulting in higher phosphorylation
of the myosin light chain [85]. VSMC phenotypic modifications are induced by SRF and control vascular tone as
well as carotid stiffness via modulation of genes coding for components of the contractile apparatus and integrins
without changes in collagen, elastin, fibronectin, and MMPs [86].
Proinflammatory Transcription Factors Ets-1 and NF-κB
Pronflammatory transcription factors Ets-1 and nuclear factor kappaB (NF-κB) associated with Ang II signaling
are both increased within the arterial wall with aging (Figure 2.1). Elevated Ets-1 activity is closely associated
with increased transcription of ET-1, MCP-1, TGF-β1, and MMP-2 within the old arterial wall [44]. Activated NF-
κB regulates the activity of MMP-2/-9, calpain-1, MCP-1, TGF-β1, and ROS, which deliver multiple signals and
potentially drive arterial aging [7,87].
ANTI-INFLAMMATORY MOLECULE SIRT1
Sirtuins, including SIRT1, are members of a small family of enzymes that require nicotinamide adenine dinu-
cleotide (NAD1
) for their deacetylase or ADP-ribosyltransferase activity (Figure 2.1). The mRNA expression of
the seven isoforms with unique subcellular localization and distinct functions in ECs is reduced with aging.
SIRT1, located predominantly in the nucleus but also found in cytoplasm, is highly expressed in vascular ECs.
Expression of SIRT1 is reduced in ECs from older versus younger mice and older versus younger healthy human
adults. Decreases in arterial expression and activity of SIRT1 with advancing age are associated with increased
acetylated eNOS, which inhibit eNOS activity and in turn contribute to vascular endothelial dysfunction [88].
The transcription factors p53, NF-κB, and forkhead box-containing protein type O subfamily (FOXO) have also
been identified as deacetylation substrates of SIRT1, thereby down-regulating stress-induced premature senes-
cence in ECs. SIRT1 also regulates oxidative stress at the chromatin level via decrease in acetylated histone H3
binding to the ShcA adapter protein P66Shc promoter region [89].
Recent reports have brought particular emphasis to the implication of sirtuins in healthy aging. Among the sir-
tuins, SIRT1 has been the most extensively characterized for its protective role in aging and cardiovascular dis-
eases, which depends upon the tissue and its degree of activation. Low to moderate over-expression of SIRT1 in
mouse hearts reduces cardiac dysfunction and senescence markers, while high levels of SIRT1 expression are
associated with cardiomyopathy and high levels of oxidative stress [90]. The protective role of SIRT1 is also
related to its ability to decrease the age-associated impairment in endothelium-dependent dilatation without
affecting endothelium-independent dilatation. Transfection of ApoE2/2
mice with a truncated inactive SIRT1
increases DNA damage, inflammation, and atherothrombotic lesions [91]. Inflammation and endothelial
12 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING
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![dysfunction shift the hemostatic balance in favor of thrombosis in aging, and that in turn, can further enhance
inflammation. Production and secretion of coagulation enzymes and cofactors as well as von Willebrand factor
by vascular cells increase as the vascular wall function deteriorates with age [92]. In addition, the age-associated
irreversible cellular senescence process, leading to a progressive decrease in plasticity and reprogramming
potential of SMCs, plays a complementary signaling role and contributes to the increase in oxidation, fibrosis,
calcification, and arterial stiffness [46,53,81].
CONCLUSION
Several new altered molecular and cellular pathways in the aging arterial remodeling have emerged and
prompted the development of selective drugs such as inhibitors of Ang II signaling or downstream molecules
MMP, MCP-1, and TGF-β; integrin antagonists; and SIRT1 activators. Preliminary studies of these interventions
provide promising results in attenuating age-related decline in physiological functions. However, several major
challenges involving simultaneous multidrug usage on several of the above-mentioned systems need to be
addressed. This may require new pharmacological design of specific drugs with careful concern for key signaling
system nodes or targeting more than one of the compensatory networks.
Acknowledgment
The authors would like to thank Robert E. Monticone for his editorial assistance in preparing this document. This research was supported by
the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
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13
REFERENCES
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- 8. EARLY VASCULAR AGING (EVA) New Directions in CardiovascularProtection Edited by PETER M. NILSSON MD PHD Professor of Cardiovascular Research, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden MICHAEL H. OLSEN MD PHD Professor in Hypertension, University of Southern Denmark, and Department of Endocrinology, Odense University Hospital, Odense, Denmark STÉPHANE LAURENT MD PHD Professor of Pharmacology, Hôpital Européen Georges Pompidou, and Paris Descartes University, Paris, France AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier
- 9. Academic Press isan imprint of Elsevier 125, London Wall, EC2Y 5AS 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright r 2015 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-801387-8 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by MPS Limited, Chennai, India www.adi-mps.com Publisher: Mica Haley Acquisition Editor: Stacy Masucci Editorial Project Manager: Shannon Stanton Production Project Manager: Lucı́a Pérez Designer: Maria Inês Cruz
- 10. List of Contributors EnricoAgabiti-Rosei Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy Tine de Backer Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium; Cardiovascular Center, University Hospital Ghent, Ghent, Belgium Luc van Bortel Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium Pierre Boutouyrie Department of Pharmacology, Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris, Paris, France; Institut National de la Santé et de la Recherche Médicale—INSERM U970, Paris, France; Université Paris-Descartes, Paris, France Michel Burnier Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland Mark Caulfield William Harvey Research Institute, NIHR Biomedical Research Unit in Cardiovascular Disease at Barts Queen Mary University of London, UK Pascal Challande Université Pierre et Marie Curie, CNRS— UMR 7190, Paris, France Pedro G. Cunha Center for the Research and Treatment of Arterial Hypertension and Cardiovascular Risk, Internal Medicine Department, Guimarães—Centro Hospitalar do Alto Ave/Minho University, Guimarães, Portugal; Life and Health Science Research Institute (ICVS), School of Health Science, University of Minho, Braga, Portugal; ICVS/3B’s— PT Government Associate Laboratory, Braga/Guimarães, Portugal Stephanie Debette Department of Neurology, University Hospital of Bordeaux, and Center for Epidemiology and Public Health—INSERM U897, University of Bordeaux, France; Department of Neurology, Boston University School of Medicine, Boston, MA, USA Andreas Edsfeldt Experimental Cardiovascular Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Cardiology, University Hospital of Skåne, Malmö/Lund, Sweden Isabel Ferreira Department of Clinical Epidemiology and Medical Technology Assessment, and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands; School of Public Health, University of Queensland, Brisbane, Australia Stanley S. Franklin Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, CA, USA Frej Fyhrquist Minerva Institute, Helsinki, Finland Panagiotis I. Georgianos Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Isabel Gonçalves Experimental Cardiovascular Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Cardiology, University Hospital of Skåne, Malmö/Lund, Sweden Dagmara Hering Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland Jens Jordan Institute of Clinical Pharmacology, Medical School Hannover, Hannover, Germany Vasilios Kotsis Hypertension Centre of Excellence, 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece Michaela Kozakova Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Roel J. van de Laar Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands Patrick Lacolley Institut National de la Santé et de la Recherche Médicale—INSERM U116; Université de Lorraine, Nancy, France Jérémy Lagrange Institut National de la Santé et de la Recherche Médicale—INSERM U116; Université de Lorraine, Nancy, France Edward G. Lakatta Laboratory of Cardiovascular Science, Intramural Research Program, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD, USA Irene Lambrinoudaki Medical School, University of Athens, Athens, Greece Stéphane Laurent Department of Pharmacology, Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris, Paris, France; Université Paris- Descartes, Paris, France; Institut National de la Santé et de la Recherche Médicale—INSERM U970, Paris, France Yimin Lu Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland Carmel M. McEniery Department Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK Krzysztof Narkiewicz Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland ix
- 11. Jan Nilsson ExperimentalCardiovascular Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden Peter M. Nilsson Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden Juan E. Ochoa Department of Cardiovascular Neural and Metabolic Sciences, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy Michael H. Olsen Cardiovascular and Metabolic Preventive Clinic, Department of Endocrinology, Center for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark; Hypertension in Africa Research Team, School for Physiology, Nutrition and Consumer Sciences, North-West University, Potchefstroom, South Africa Carl J. Östgren Department of Medical and Health Sciences, Linköping University, Linköping, Sweden Carlo Palombo Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy Gianfranco Parati Department of Health Sciences, University of Milano-Bicocca, Milan, Italy; Department of Cardiovascular Neural and Metabolic Sciences, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy Veronique Regnault Institut National de la Santé et de la Recherche Médicale—INSERM U116; Université de Lorraine, Nancy, France Meixia Ren William Harvey Research Institute, Centre for Clinical Pharmacology, Queen Mary University of London, UK Ernst Rietzschel Departments of Cardiovascular Diseases & Public Health, Ghent University, Ghent, Belgium; Department of Cardiology, Ghent University Hospital, Ghent, Belgium Damiano Rizzoni Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy Paolo Salvi Department of Cardiovascular Neural and Metabolic Sciences, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy Pantelis A. Sarafidis Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Giuseppe Schillaci Department of Medicine, University of Perugia, Perugia, Italy; Unit of Internal Medicine, Terni University Hospital, Terni, Italy Arno Schmidt-Truksäss Department of Sport, Exercise and Health, Sport and Exercise Medicine, University of Basel, Basel, Switzerland Angelo Scuteri Hospital San Raffaele Pisana, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy Patrick Segers IBiTech-bioMMeda, iMinds Medical IT, Ghent University, Gent, Belgium Thomas Sehestedt Department of Cardiology, Herlev Hospital, Copenhagen, Denmark Shweta Shukla Laboratory of Cardiovascular Science, Intramural Research Program, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD, USA Trine K. Sønder Heymans Institute of Pharmacology and Complications Research, Ghent University, Ghent, Belgium; Steno Diabetes Center, Gentofte, Denmark Ulrike M. Steckelings Department of Cardiovascular and Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark Coen D.A. Stehouwer Department of Internal Medicine and Cardiovascular Research Institute (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands Costas Tsioufis 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece Charalambos Vlachopoulos Hypertension Unit and Peripheral Vessels Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece Mingyi Wang Laboratory of Cardiovascular Sciences Biomedical Research Center, Baltimore, MD, USA Thomas Weber Cardiology Department, Klinikum Wels- Grieskirchen, Wels, Austria Kate Witkowska William Harvey Research Institute, Centre for Clinical Pharmacology, Queen Mary University of London, UK Panagiotis Xaplanteris Hypertension Unit and Peripheral Vessels Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece x LIST OF CONTRIBUTORS
- 12. Preface We welcome thereader to this book on different aspects of Early Vascular Aging (EVA), a concept that has attracted considerable attention since it was first described in 2008. A number of skilled authors have contributed to provide a multifaceted description of the pathophysiological and clinical aspects that are associated with EVA. Previous research has for dec- ades described and investigated atherosclerosis, a pro- cess that starts in the intima layer of the arterial wall and becomes proximal to many cardiovascular events caused by athero-thrombotic disease. As the core com- ponent of EVA is arterial stiffness, arteriosclerosis, which is mainly influenced by morphological changes in the arterial media layer, but also in other layers, we have focused on different characteristics and mechan- isms associated with stiffness of the large elastic arter- ies. We also consider EVA based on an integrated view linking the macro- with the microcirculation. This is because hemodynamic forces influenced by stiffness may also cause harm to the peripheral smaller vessels due to the increased pulsatile energy that is transmitted, for example, in the brain. Another aspect of a more integrated approach identifies important contributing factors for EVA also from the intima (endothelial dysfunction) and the adventitia (impaired function of vasa vasorum and innervation, accompanied by increased secretion of cytokines from the perivascu- lar adipose tissue causing local inflammation) when impaired glucose metabolism could further contribute to stiffening by glycosylation. Therefore, we consider EVA to be a fruitful scientific concept to promote research on early changes of the arterial wall, pro- grammed already in utero and early life and influenced by genetic and environmental factors. As meta- analyses have documented that arterial stiffness (increased aortic pulse wave velocity, aPWV) is an independent risk marker for future cardiovascular risk and total mortality, adjusted for conventional risk fac- tors, we consider it of importance to find new ways to find, diagnose, and treat subjects with signs of EVA. Still however, neither an exact definition nor a targeted treatment exists for EVA, but several attempts are being made to find such alternatives. We therefore invite the reader to contribute to the lively discussion on EVA with data from different populations and eth- nic groups, as well as with data from basic and clinical science. This could contribute to early detection of at- risk individuals, for example, from at-risk families with early onset cardiometabolic disease, for preven- tion based on improved life style as well as drug ther- apy when needed. This is not to deny the importance of atherosclerosis and the evidence-based methods that exist to prevent cardiovascular events by control of hypertension and hyperlipidemia as well as smoking cessation, but we consider that EVA is a feature start- ing early in life and that later in life components of arteriosclerosis and atherosclerosis will be intertwined in further promoting cardiovascular disease risk. In an historical perspective, the interest in arterial function and stiffness contributing to hemodynamic changes predates the clinical measurement of blood pressure and diagnosis of hypertension as we know it. In London, the physician Fredrik Akbar Mahomed car- ried out studies on pulse wave properties in arteria radialis with his own sphygmograph and published in 1877: It is very common to meet with people apparently in good health who have no albumen in the urine, who constantly present a condition of high arterial tension when examined by the aid of the sphygmograph. [1] We therefore date the interest in large arteries and stiffness to an era before clinical hypertension was rec- ognized [2], and thus the EVA concept [3 5] attempts to bridge more than a century to revive the importance of large arteries and their properties in cardiovascular medicine. Peter M. Nilsson Malmö, Sweden Michael H. Olsen Odense, Denmark Stéphane Laurent Paris, France xi
- 13. References [1] Mahomed FA.Remarks on arterio-capillary fibrosis and its clini- cal recognition. Lancet 1877;110(2816):232 4. [2] Riva-Rocci S. Un nuovo sfigmomanometro. Gazz Med Torino 1896;50 51:1001 7. [3] Nilsson PM, Lurbe E, Laurent S. The early life origin of vascular ageing and cardiovascular risk. J Hypertens 2008;26:1049 57. [4] Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and preven- tion. Hypertension 2009;54:3 10. [5] Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K, Parati G, et al. Early vascular ageing in translation: from labora- tory investigations to clinical applications in cardiovascular pre- vention. J Hypertens 2013;31:1517 26. Frederick H. H. Akbar Mahomed (c. 1849 1884), arterial studies Scipione Riva-Rocci (1863 1937), measurement of systolic blood pressure xii PREFACE
- 14. C H AP T E R 1 Historical Aspects and Biology of Aging Peter M. Nilsson Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden Aging is a universal finding in humans, afflicting biological processes as well as maturation and deterioration of organ function. There exist a number of theories on how aging is programmed and develops as presented in gerontology, the science of normal aging. Not only the “wear and tear” hypothesis exists but also aging models dependent on the influence of oxidative stress, metabolic processes, and the accumulation of genetic damage on the DNA and impaired genetic repair functions [1]. Modern discoveries point to the role of longevity-regulating genes, so-called “gerontogenes” [2]. These gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function linked to metabolism, and genes regulating cellular senescence and programmed cell death (apoptosis) [2]. Intensive research is directed to understand what regulates aging and how to control this, not at least apoptosis, of vital importance to understand organ develop- ment and changes in health and disease. The maximum lifespan recorded was 122 years for a French woman (Jean Calment, France, 1875 1977). Even if it is very hard to disentangle the different influences on the aging process and to judge upon the accuracy of the different hypotheses to explain human aging in general, it comes natural to view aging in its evolutionary context as all aspects of human biology, and even cognitive function, are supposed to be influenced by evolutionary selection mechanisms during millennia perspectives. EVOLUTIONARY TRAITS, GENES, AND THE ENVIRONMENT INFLUENCING AGING From an evolutionary perspective the lifespan of mammals has been formed by selective processes based on genetic regulation of survival and reproduction in relation to available nutrition, environmental hazards, and competition for resources. According to the “disposable soma hypothesis” by Kirkwood [3] there exists a trade-off between maintenance of bodily functions, depending on energy investments, and the costs of reproduction, especially for women. This is why, according to this hypothesis, women with a higher number of offspring will be at increased risk for a shorter lifespan as compared to women with fewer offspring, if basal health and social conditions tend to be equal, as studied in British noble families over many centuries [4]. This is also influenced by nutritional resources, as reproductive capacity in women tends to cease during periods of famine and starvation. Behind such traits there must be genetic regulators, as evolution works via genetic adaption and fitness in relation to a changing environment. A further support for the genetic influence on longevity is the family resem- blance of longevity as well as risk of some chronic disease conditions that tend to run in families, that is, clusters of cardiovascular disease [5] and metabolic abnormalities. According to a number of studies the genetic explana- tion of longevity is approximately 25% [6]. This leaves a substantial proportion of longevity to the influence of environmental factors or to epigenetic mechanisms (gene environmental interactions). It is still unclear if true life-prolonging genes exist in humans as in other less-developed organisms (Caenorhabditis elegans), or if a long lifespan is a marker of the less strong impact or lack of disease-related genes in some individuals. According to 1 Early Vascular Aging (EVA). © 2015 Elsevier Inc. All rights reserved.
- 15. environmental factors, thereare many such detrimental factors well known to decrease lifespan, for example, smoking, infectious disease, and malnutrition, but the only environmental factor known to prolong life in mammals, at least in rodents and monkeys, is continuous calorie restriction [7]. This is believed to exert similar effects in humans but still not proven. Nevertheless some individuals have adopted a lifestyle based on calorie restriction and balanced physical activity, hoping for a prolonged life. CHANGES DURING THE TWENTIETH CENTURY IN LIFE EXPECTANCY There is no doubt that the rapid increase in longevity during the past twentieth century is an indication of the strong influence of environmental factors on human lifespan, reflecting better nutrition and housing, improved hygiene and conditions in early life, as well as the progress of healthcare and improved medical treatment, even if temporary setbacks have also been noticed, for example, in Russia during the 1990s [8]. The negative socioeconomic changes for many citizens in Russia during this period could be one compo- nent of the increased cardiovascular risk based on gene environmental interactions in high-risk popula- tions [9]. On the other hand, it is still necessary to understand the biology (and genetics) behind the aging process, as there are still many examples of differential aging also in developed countries. A proof of the role of genetic influences on aging and shortened lifespan are the rare conditions of Hutchinson Gilford progeria in children and Werner’s syndrome in middle-aged subjects [10]. Even if these rare conditions are not possible to causally treat today, they represent an opportunity to learn more about biological changes taking place during the aging process, especially when it is upregulated in the progeria syndromes with shortened lifespan. EARLY LIFE PROGRAMMING EFFECTS Human life starts at the conception followed by a growth during 9 months in fetal life in utero when organs are formed and developed based on numerous cell divisions under genetic regulation. Nutritional factors are of great importance for this process, as mediated by the feto-placental unit and influenced by maternal dietary intakes. For more than 30 years now, researchers have documented the importance of fetal growth and birth weight for bodily development and health also in adult life. Starting with early observations from northern Norway by Forsdahl [11] and by Gennser [12] in Sweden, David Barker and many other colleagues developed a concept based on the detrimental health consequences of fetal growth retardation leading to the small-for- gestational age (SGA) phenotype in newborn babies. This condition in early life was associated with increased levels of cardiovascular risk factors (hypertension, dyslipidemia, and hyperglycemia) and even overt type 2 diabetes in adult life, but also with impaired neurocognitive developments and a number of other adverse health conditions, summarized in the so-called “Barker hypothesis” [13]. In more recent years a new paradigm has evolved with a focus not only on fetal growth and birth weight as outcomes but also on postnatal growth patterns. Of special importance for adult health is the combination of impaired fetal growth, causing SGA at birth, combined with a rapid catch-up growth pattern in the first few years of life. This has been named the “mismatch” growth pattern when different organs are programmed in utero for a life with scarce resources and calorie depletion but later on the newborn child will experience the opposite, an environment with a surplus of calories and nutritional abundance. This may negatively impact on organ development and increase the risk of cardiometabolic disturbances in adult life. The most well-known protagonists of the “mismatch” hypothesis today are Peter Gluckman and Mark Hanson, with important reviews on the topic [14]. They are both active in the “Developmental Origins of Health and Disease” (DOHaD) society, to further explore the mismatch hypothesis. An even more recent hypothesis of early life programming of adult disease risk is linked to the impact on child gut microbiota from the mother during delivery [15], as a detrimental gut microbiota pattern could be one factor increasing the risk of obesity in adult life and adverse health conditions such as cardiovascular disease [16] and type 2 diabetes [17]. It is believed that the mother’s gut bacteria will normally colonize the gastrointestinal system of the newborn child and that this will protect from overgrowth of more deleterious skin bacteria that could be associated with later disease risk [15]. 2 1. HISTORICAL ASPECTS AND BIOLOGY OF AGING EARLY VASCULAR AGING (EVA)
- 16. It is likelythat such influences in early life from nutrition, growth patterns, and microbiota patterning could also impact on aging in general and/or age-related medical conditions. These include not only defined chronic disease but also the increasing frailty, that is, related to sarcopenia and osteoporosis in old age, as well as cognitive decline [18]. Newer studies on the life of centenarians have also highlighted the role of early life influences, for example, the longevity associated with being born to younger mothers (first-born) when siblings within the same family are compared [19]. There also seem to exist large gender differences found in longevity determinants for males and females, suggesting a higher importance of occupation history for male centenarians as well as a higher importance of home environment history for female centenarians [19]. VASCULAR AGING IN PERSPECTIVE What implications do these observations have for the concept of early vascular aging (EVA) with increased arterial stiffness as a central characteristic [20]? First of all, EVA is likely to be an expression of biological aging in general and some of the mechanisms regulating aging in other organs must also be appli- cable to the vascular tissue, especially in the arterial wall. This is believed to be possible to estimate by measuring leukocyte telomere length (LTL), a proposed marker of biological aging as LTL tends to shorten with every cell division. However, in a large population-based study, the Asklepios study in Belgium, no association between pulse wave velocity (PWV), a marker of arterial stiffness as the core characteristic of EVA, and LTL was seen in a cross-sectional analysis [21]. On the other hand, some associations were seen with cardiac function, which is why the authors concluded that in a generally healthy, young to middle- aged population, LTL is not related to left ventricular (LV) mass or systolic function, but might be associated with an altered LV filling pattern, especially in women. The Asklepios study purposefully selected healthy individuals for screening. The findings of this large and more recent Belgian study contradicts earlier observations from a smaller French study [22], when it was concluded that LTL provides an additional account to chronological age with regard to variations in both pulse pressure and PWV among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and PWV, which both are indices of large artery stiffness (arteriosclerosis). The longer telomere length in women of that study suggests that for a given chronological age, biological aging of men is more advanced than that of women [22]. How to resolve these contradictory findings? It is believed that cross-sectional analyses of LTL in relation to organ function is probably not enough. Of even greater importance could be to evaluate relationship with telo- mere attrition rate based on repeated measurements of LTL over a time period. Few studies have applied this more laborious and costly method, and this is why more studies are needed with precise methods for measuring LTL and also attrition rate over time [23]. Before such data are available it is hard to judge on the true relation- ship between LTL and telomere biology, as a marker of aging, and arterial stiffness representing vascular aging. On the other hand, there are numerous studies to show associations between shorter telomeres and vascular disease based on atherosclerosis, as recently summarized [24]. NEW MODELS AND INTERVENTIONS TO INFLUENCE AGING If a deeper understanding can be achieved of the aging process in general, with its vascular implications, this could also lead to the establishment of new experimental models to test the reversibility (if any) of these pro- cesses. Molecules that suppress these age-related changes would provide an excellent medical intervention target for vascular disorders. Mammalian Sir2 (SIRT1, a NAD1 -dependent deacetylase), previously shown to extend the lifespan of lower organisms, is a promising target molecule to influence some aspects of vascular aging. The influence of SIRT1 in various pathophysiological processes of vascular aging has been summarized and Wang et al. proposed that SIRT1 and its activators can become novel therapeutic targets for age-related vascular disease [25]. Time will tell if this intervention model will be able to shed new light on the aging process in general and vascular aging in particular (Table 1.1). 3 NEW MODELS AND INTERVENTIONS TO INFLUENCE AGING EARLY VASCULAR AGING (EVA)
- 17. Acknowledgment This review wassupported by a grant from the Research Council of Sweden for studies on early vascular aging in the population. References [1] Kolovou GD, Kolovou V, Mavrogeni S. We are ageing. Biomed Res Int 2014;2014:808307. [2] Moskalev AA, Aliper AM, Smit-McBride Z, Buzdin A, Zhavoronkov A. Genetics and epigenetics of aging and longevity. Cell Cycle 2014;13:1063 77. [3] Kirkwood TB, Rose MR. Evolution of senescence: late survival sacrificed for reproduction. Philos Trans R Soc Lond B Biol Sci 1991;332:15 24. [4] Westendorp RG, Kirkwood TB. Human longevity at the cost of reproductive success. Nature 1998;396:743 6. [5] Nilsson PM, Nilsson JA, Berglund G. Family burden of cardiovascular mortality: risk implications for offspring in a national register linkage study based upon the Malmö Preventive Project. J Intern Med 2004;255:229 35. [6] Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet 2013;132:1323 38. [7] Smith Jr DL, Nagy TR, Allison DB. Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest 2010;40:440 50. [8] Plavinski SL, Plavinskaya SI, Klimov AN. Social factors and increase in mortality in Russia in the 1990s: prospective cohort study. BMJ 2003;326:1240 2. [9] Nilsson PM. Genetic and environmental determinants of early vascular ageing (EVA). Curr Vasc Pharmacol 2012;10:700 1. [10] Ding SL, Shen CY. Model of human aging: recent findings on Werner’s and Hutchinson Gilford progeria syndromes. Clin Interv Aging 2008;3:431 44. [11] Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med 1977;31:91 5. [12] Gennser G, Rymark P, Isberg PE. Low birth weight and risk of high blood pressure in adulthood. Br Med J (Clin Res Ed) 1988;296:1498 500. [13] Cooper C, Phillips D, Osmond C, Fall C, Eriksson J. David James Purslove Barker: clinician, scientist and father of the “fetal origins hypothesis”. J Dev Orig Health Dis 2014;5:161 3. [14] Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008;359:61 73. [15] Reinhardt C, Reigstad CS, Bäckhed F. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr 2009;48:249 56. [16] Ettinger R, MacDonald K, Reid G, Burton JP. The influence of the human microbiome and probiotics on cardiovascular health. Gut Microbes 2014;5:719 28. [17] Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut 2014;63:1513 21. [18] Langie SA, Lara J, Mathers JC. Early determinants of the ageing trajectory. Best Pract Res Clin Endocrinol Metab 2012;26:613 26. [19] Gavrilov LA, Gavrilova NS. New developments in the biodemography of aging and longevity. Gerontology 2014; Dec 20. [Epub ahead of print] PubMed PMID: ,25531147.. [20] Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K, Parati G, et al. Early vascular ageing in translation: from laboratory investi- gations to clinical applications in cardiovascular prevention. J Hypertens 2013;31:1517 26. TABLE 1.1 Some Factors of Importance to the Shaping of Human Aging and Longevity Genetic programming, based on evolutionary selection Epigenetic influences (gene environmental interaction and imprinting) Early life programming (nutrition, growth rates, neurocognitive function) Family patterns (sibling rank, age of parents, shared microbiota) Adult lifestyle (smoking, nutrition, physical activity) Telomere biology Health problems and disease Medical treatment and interventions Societal factors and social support Secular trends 4 1. HISTORICAL ASPECTS AND BIOLOGY OF AGING EARLY VASCULAR AGING (EVA)
- 18. [21] Denil SL,Rietzschel ER, De Buyzere ML, Van Daele CM, Segers P, De Bacquer D, et al. Asklepios investigators on cross-sectional associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study. PLoS One 2014; 9(12):e115071. [22] Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J, et al. Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension 2001;37(2 Pt 2):381 5. [23] Nilsson PM. Mediterranean diet and telomere length. BMJ 2014;349:g6843 ,http://dx.doi.org/10.1136/bmj.g6843.. PubMed PMID: ,25467755.. [24] Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg 2010;40:17 26. [25] Wang F, Chen HZ, Lv X, Liu DP. SIRT1 as a novel potential treatment target for vascular aging and age-related vascular diseases. Curr Mol Med 2013;13:155 64. EARLY VASCULAR AGING (EVA) 5 REFERENCES
- 19. C H AP T E R 2 Cellular and Molecular Determinants of Arterial Aging Patrick Lacolleya , Pascal Challandeb , Veronique Regnaulta , Edward G. Lakattac and Mingyi Wangd a Institut National de la Santé et de la Recherche Médicale—INSERM U1116; Université de Lorraine, Nancy, France; b Université Pierre et Marie Curie, CNRS—UMR 7190, Paris, France; c Laboratory of Cardiovascular Science, Intramural Research Program, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD, USA; d Laboratory of Cardiovascular Sciences Biomedical Research Center, Baltimore, MD, USA INTRODUCTION The aging of the world population has progressed unabated as more adults are surviving into their senior years. The heterogeneity of aging phenotypes results from genetic and epigenetic impacts on different cell types and tissues throughout a lifetime [1]. Importantly, arterial aging is intertwined with hypertension and atherosclerosis at the molecular, cellular, vascular, and clinical levels because the aged arterial wall is fertile soil for their pathogenesis. Age-associated arterial diseases account for a large part of total mortality, approximately 29% of all deaths. Hypertension is a major factor to promote arterial aging. The prevalence of hypertension is around 50% and 60% over 60 and 70 years of age, respectively [2]. It is higher in men than in women before 50 years of age, whereas in older persons, the sex difference in prevalence of hypertension is greater in women than in men [3]. The prevalence of hypertension is similar in various regions of the world [4], whereas the prevalence of stroke is 3.5-fold higher in low-income than in middle- and high-income countries [5]. Arteriosclerosis is defined as an age-associated stiffening and dilatation of the large arteries. Atherosclerosis represents the leading cause of mortality and is characterized by four major steps: (i) an initial endothelial activa- tion by hemodynamic factors and dyslipidemia followed by leucocyte transmigration and activation involving cytokines and innate or adaptive immunity; (ii) a promotion step, which includes development of foam cells and lipoprotein retention; (iii) a progression step by growth of complex plaques; and (iv) plaque destabilization and thrombosis. Atherosclerosis within the arterial wall leads to inflammation, accumulation of fibronectin, collagen deposition, and fibrosis. Aging is characterized by chronically elevated levels of low-grade circulating inflammatory molecules such as monocyte chemoattractant protein-1 (MCP-1) [6]. In particular, the interactions of environmental, systemic, and local chronic stress signals are conferred to vascular cells and the matrix, which insidiously facilitate arterial adverse remodeling through proinflammatory signaling such as the angiotensin II (Ang II) signaling cascade with aging. This process leads to endothelial disruption, thrombosis, senescence, glycoxidation, fibrosis, elastin fragmentation, calcification, and amyloidosis [1,7 9]. Importantly, this proinflammatory response accelerates the cardiovascular burden of both hypertension and atherosclerosis in the elderly [7,9]. This review focuses upon the key molecules involved in inflammatory mechanisms and pathways that are implicated in the aging of the arte- rial wall (Figure 2.1). 7 Early Vascular Aging (EVA). © 2015 Elsevier Inc. All rights reserved.
- 20. CYTOSKELETAL AND CONTRACTILEPROTEINS IN THE AGING ARTERIAL WALL Cytoskeletal Proteins Desmin and vimentin are the main components of intermediate filaments implicated in mechanotransduc- tion (Figure 2.1). Both desmin and vimentin are generally found to be decreased with advancing age in rat smooth muscle cells (SMCs) [10 13]. The mechanical properties of SMCs through cytoskeletal proteins contrib- ute to the increased stiffness of the aorta in old versus young monkeys [14]. Desmin is required in the dilatory and contractile functions of SMCs and provides an efficacious interaction between the cytoskeletal and the con- tractile elements to maintain the mechanical integrity of SMCs. In old SMCs there is a shift toward small vimentin fragments, and co-localization with calpain-1 argues for calcium-dependent vimentin cleavage by calpain-1 [15]. Contractile Proteins Smooth muscle (SM) myosin heavy-chain content/isoform expression is the most discriminant marker of fully differentiated SMCs (Figure 2.1). Alteration in SM myosin has been reported in aged rats. In SMCs cul- tured from 30-month-old Fischer 344XNB rats or 24-month-old Wistar rats, SM myosin is decreased compared to SMCs isolated from 6-month-old rats [12,13,16]. SMCs freshly isolated from 18-month-old Wistar rat aortae showed percentages of SM-myosin-positive cells similar to those observed in newborn and young adult rat SMCs [10]. Higher tissue content of myosin heavy chain and a higher ratio of SM1/SM2 isoforms have been reported in aortae of 36-month-old Fischer 344/NNiaHSd X Brown Norway/BiNia compared to those of 6-month-old rats [17]. Interestingly, embryonic myosin in SMCs is increased in aged thickened intima in humans [18]. In addition, the contractile regulatory light-chain MyL9 is overexpressed in endothelial layers of aging rats and is associated with an increase of endothelial cell (EC) contraction resulting in endothelial hyperpermeability [19]. Cellular and molecular determinants of arterial aging RAAS ROS/RNS NO MCP-1 MMPs MFG-E8 Adhesion molecules Contractile proteins Cytoskeletal proteins CArG Box NF-κB Ets-1 SIRT1 FoxO3 Autocrine/paracrine /Juxtacrine proinflammatory Shift Intima media thickness (IMT) Fibrosis Elastin fragmentation Calcification Glycoxidation Stiffening Aging: Stiffening↑ Systolic blood pressure (SBP)↑ Endothelial Dysfunction Signaling loop Cellular phenotype Vascular phenotype Vascular function Clinical phenotype FIGURE 2.1 Diagram of cellular and molecular determinants of arterial aging. 8 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING EARLY VASCULAR AGING (EVA)
- 21. CELLULAR MATRIX STRUCTUREIN THE AGING ARTERIAL WALL It is known that the elastin/collagen ratio plays an important role in arterial mechanical properties [20]. Changes in both content and organization of elastin and collagen fibers influence the arterial wall with age. When expressed as a percentage, elastin percentage is decreased while collagen percentage is increased, which causes a net decrease in the elastin/collagen ratio with aging [20]. The bulk of the elastin is highly susceptible to age-related changes, which involve an increase in associated polar amino acids, the binding and accumulation of calcium and lipids, and fragmentation due to enzymatic degradation or fatigue processes [20,21]. Advanced glycation end- products (AGEs)-mediated cross-linking of elastin increases with age in the human aorta [22]. By contrast, collagen fibrils become organized into multibranched bundles and stiffen [23]. PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR EVENTS IN THE AGING ARTERIAL WALL The Renin Angiotensin Aldosterone System The components of the renin angiotensin aldosterone system (RAAS) are important aspects of the proinflam- matory system (Figure 2.1), including angiotensin converting enzyme (ACE), Ang II, and its receptor AT1. The transcription, translation, and activity of ACE markedly increase within both ECs and vascular SMCs (VSMCs) in the arterial wall with aging in rodents, nonhuman primates, and humans [18,24,25]. In addition, an alternative angiotensin convertase, chymase, increases within the arterial wall with aging [25]. As a result, the cleaved prod- uct, Ang II protein, becomes markedly increased, particularly in the thickened intima of rats, nonhuman primates, and humans [15,18,25 27]. Furthermore, the Ang II receptor, AT1, is up-regulated within the old arterial wall [18]. Ang II stimulates aldosterone secretion. The mineralocorticoid receptor (MR) expression is increased in the arterial wall with aging [28,29]. Furthermore, aging increases the sensitivity of MR to Aldo. Increased MR activity in aged rats promotes a proinflammatory phenotype via an extracellular signal-regulated kinase 1/2/mitogen- activated protein kinase/epidermal growth factor receptor (ERK-1/2/MAPK/EGFR)-dependent pathway, con- tributing to the synthetic phenotypic shift of SMCs within the aging arterial wall [28]. In addition, aldosterone mediates an increase in the expression of EGFR in SMCs with aging, further reinforcing its proinflammatory effects [28]. Notably, cardiotrophin-1 (CT-1), a proinflammatory cytokine overexpressed in SMCs by aldosterone [30], also contributes to vascular aging because CT-1 treatment increases SMC proliferation and collagen produc- tion, whereas its invalidation increases longevity in mice [31]. Increased activation of the RAAS and an increase in oxidative stress that contributes to arterial proinflammation are both implicated in age-related arterial remodeling. Chronic infusion of a physiologically relevant dose of Ang II to adult rats (8-months-old) increases expression of molecules that comprise the proinflammatory profile, that is, matrix metalloproteinase type II (MMP-2), MCP-1, calpain-1, transforming growth factor-β1 (TGF-β1), and nicotin- amide adenine dinucleotide phosphate (NADPH) oxidase. The infusion also elicits the age-associated increase in aortic and coronary structural manifestations, that is, intimal and media thickening of old (30-month-old), untreated arteries [27]. In addition, the α-adrenergic receptor agonist, phenylephrine, increases arterial Ang II pro- tein, causing MMP-2 activation and intimal and medial thickening [27]. In contrast, chronic ACE inhibition and AT1 receptor blockade, beginning at an early age, markedly inhibit the expression of proinflammatory molecules and delay the progression of age-associated aortic remodeling [24,32]. Interestingly, long-term AT1 blockade improves endothelial function, decreases blood pressure, and doubles the life span of hypertensive rats similar to normotensive animals [33]. Disruption of the AT1 receptor retards arterial inflammation, promotes longevity, and improves survival after myocardial infarction in mice [34]. Proteinases Matrix Metalloproteinases An important component of age-associated vascular remodeling is degradation and resynthesis of extracellular matrix (ECM) (Figure 2.1). Specialized enzymes known as matrix metalloproteinases (MMPs) mediate the degra- dation process. Among MMPs, the MMP-2 mRNA and protein increase in the aortic walls of aged rodents, non- human primates, and humans and is also activated by Ang II signaling [25,27,35 38]. The increased MMP-2 activity is mainly seen within the thickened intima and the inner media in rodents and monkeys [25,39]. The 9 PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR EVENTS IN THE AGING ARTERIAL WALL EARLY VASCULAR AGING (EVA)
- 22. enhanced MMP-2/-9 activityis also observed in the aortae from human autopsy in the “grossly normal vessels” with aging [18]. An increase of MMP-2/-9 activity is attributable to not only an enhanced transcription and trans- lation, but also to an imbalance of its activators, membrane-type-1 matrix metalloproteinase (MT1-MMP), urine plasminogen activator, and tissue plasminogen activator and inhibitors, tissue inhibitor of MMP-2 (TIMP-2), and plasminogen activator inhibitor [25,39]. Notably, the micro-processing of extracellular bioactive molecules via MMP activation likely facilitates the ini- tiation and progression of hypertension. Activated MMP-2 increases the bioavailability of vasoconstrictors such as big endothelin-1 (ET-1), while decreasing the vasodilator such as adventitial calcitonin gene-related peptide (CGRP) and endothelial NO-synthase enzyme (eNOS) [7,40,41]. MMP-2-7/-9 reduces the density of the extracel- lular domain of β(2)-adrenergic receptor in blood vessels and enhances the arteriolar tone [42,43]. Interestingly, age-associated arterial remodeling due to arterial wall collagen deposition and elastin fragmenta- tion known as elastolysis is associated with an increase in arterial MMP activation. Chronic administration of a broad-spectrum MMP inhibitor markedly blunts the age-associated increases in aortic gelatinase and interstitial collagenase activity and reduces the elastin network degeneration, collagen deposition, MCP-1 expression, TGF- β1 activation, and Smad-2/-3 phosphorylation [44]. Importantly, MMP inhibition also substantially diminishes pro-ET-1 activation and down-regulates Ets-1 expression [44]. Calpain-1 Calpain-1 is a calcium-dependent intracellular proteinase and is an important activator of MMP-2 [45]. Transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic SMCs from old rats compared to young animals [15]. Co-localized calpain-1 and Ang II are within the aged arterial wall [15]. Ang II induces calpain-1 expression in the aortic walls in vivo and aortic rings ex vivo and SMCs in vitro [15]. Over-expression of calpain-1 in young SMCs leads to cleavage of intact vimentin, an increase of migratory capacity, and calcification mimicking that of old SMCs [15]. In addition, communication between MMP-2 and calpain-1 is observed in aged arterial walls or SMCs. Aging induces both MMP-2 and calpain-1 expression and activation in the arterial wall [45]. Co-localization of calpain-1 and MMP-2 are observed within old rat SMCs [45]. Over-expression of calpain-1 induces MMP-2 transcription, translation, and activity, in part, due to increasing the ratio of MT1-MMPs to TIMP-2 [45]. These effects of calpain-1 over-expression-induced MMP-2 activation are linked to increased TGFβ-1/Smad-2/-3 signaling, and collagen I, II, and III production [38,45]. Cross-talk of two proteases, calpain-1 and MMP-2, synergistically modu- lates ECM remodeling and facilitates calcification by enhancing collagen production in SMCs with aging [45]. A switch from a de-differentiated to a pro-calcificatory phenotype of SMCs also induces vascular calcification with advancing age [46]. Transforming Growth Factor-β1 Arterial TGF-β1 mRNA and protein are abundantly present in the aged arterial wall (Figure 2.1) [27,38]. Co-expression of both TGF-β1 and TGF-β1 receptor II (TβIIR) proteins increases in rat aortae at 30 versus 8 months of age [38]. TGF-β1 plays an important role in arterial fibrosis [27,29,37,38]. TGF-β1 expression is tempo-spatially associated with the collagen expression and local fibrosis in the aging arterial wall [27,39]. In vitro studies show that ECs and VSMCs treated with TGF-β1 increase collagen types I and III mRNA, and this is attenuated by a TβIIR blocker [47,48]. Importantly, enhanced expression of active TGF-β1 and collagen deposition in the thick- ened vascular wall of aged rats is, in part, produced by exaggerated MMP-2 activation of latent transforming protein-1 [38]. Furthermore, the increased MCP-1 co-localizes with TGF-β1, which suggests an interaction may exist between MCP-1 production and TGF-β1 activity [37]. Indeed, TGF-β1 transcription, translation, and activity increase in VSMCs treated in response to MCP-1 and enhance production of ECM [37]. Monocyte Chemoattractant Protein-1 MCP-1, a downstream molecule of Ang II signaling, is a potent inflammatory cytokine (Figure 2.1). With aging, MCP-1 mRNA increases within aortic walls in FXBN rats [49]. The increased MCP-1 protein is predomi- nantly localized to the thickened intima [49]. The increased MCP-1 also co-localizes with TGF-β1, suggesting an interaction between MCP-1 production and TGF-β1 activity [37]. Indeed, TGF-β1 transcription and translation increase in SMCs treated with MCP-1 and exposure of SMCs to MCP-1 increases TGF-β1 activity [37]. Thus, 10 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING EARLY VASCULAR AGING (EVA)
- 23. MCP-1 signaling alsoinitiates the fibrosis of aging. Notably, MCP-1 dimerization is necessary for chemoattractant activity [50]. MCP-1 forms dimers at local high concentrations such as in the aged arterial wall, which is likely to strongly attract the invasion of SMCs [26]. Reactive Oxygen Species and NO Bioavailability Non-phagocytic NAD(P)H oxidase, which generates arterial cell reactive oxygen species (ROS) in the vascular system, is activated by Ang II signaling (Figure 2.1). NAD(P)H oxidase membrane-bound components p22phox and gp91phox are increased in the endothelium of aortae from old versus young rats [51]. Further, cytosolic com- ponent p47phox also increases in the arterial wall with aging in rodents [52,53]. Importantly, anti-oxidant Cu/Zn superoxide dismutase (SOD1), Mg SOD (SOD2), and ECM superoxide dismutase (ECM-SOD/SOD3) decrease in the arterial wall, which accompanies aging in rats [54 57]. Indeed, with aging, a loss of balance between oxidase and dismutase has been observed in the coronary arterial wall and aortic wall of rats, consequently resulting in an increase of superoxide and hydrogen superoxides [58 61]. Nitric oxide (NO) is a diffusible gas that can act as an intracellular and intercellular messenger in the arterial wall that is avidly scavenged by superoxide anions. The main source of NO is the ECs in the arterial wall. Endothelial production of NO becomes reduced with advancing age [55,62,63]. NO is generated from the meta- bolic conversion of L-arginine into L-citrulline by the activity of the NOS. Two major classes of NOSs have been described in the vascular system. One isoform is constitutively expressed (eNOS) under basal conditions and is involved in the endothelium-dependent vasodilation response. Another isoform, iNOS, is inducible by inflamma- tion [64]. While iNOS is absent in the aortic segments of young rats, a marked expression of the iNOS protein is observed in segments of aging rats [64]. The expression of both eNOS and iNOS is altered in the arterial wall with aging [55,64,65]. Augmented release of ROS subsequently inactivates NO with increasing age [61]. Reactive nitrogen species are also important modulators of NO bioavailability [66]. The interaction of NO and free radicals will result in subse- quent formation of peroxynitrite (ONOO ). Strong experimental evidence has recently been presented for a close association between the formation of ONOO and age-associated vascular endothelial dysfunction [66]. The aging arterial wall is a frequent target of modifications by reactive oxidative compounds such as NADPH oxidase and reducing sugars known as glycoxidation [8,67 70]. AGEs are easily formed by a reaction between sugar chains and biologic amines of oxidized collagen. Stabilized glycated proteins accumulate over a lifetime and contribute to age-associated multiple structural and physiologic changes in the vascular system such as increased vascular stiffness, endothelial dysfunction, and inflammation [8]. MFG-E8, Fibronectin, and Integrin Receptors MFG-E8 and Its Fragment Medin A high-throughput proteomic screening identified milk fat globule-EGF-8 (MFG-E8) (Figure 2.1), a cell adhe- sion protein, as an important Ang II signaling signature of aging arterial walls [26]. Levels of arterial MFG-E8 and its degradation fragment, medin, both increase and accumulate in the aorta with aging in rodents, nonhu- man primates, and humans [26,71,72]. MFG-E8 is induced by Ang II and itself induces the expression of MCP-1 in SMCs within the aortic wall of old rats [26]. Integrins comprise a widely distributed family of cell surface α/β heterodimeric adhesion receptors that bind cells to components of the ECM such as fibronectin. They act as sensing and signaling transmembrane receptors. Integrin α5β1 and αvβ3/5 expressions are increased in the arterial wall of old hypertensive rats, contributing to arterial stiffening [73,74]. Co-expression and increased physical interaction of MFG-E8 and integrin αvβ5 occur with aging in both the rat aortic wall in vivo and in SMC in vitro, promoting SMC invasion and proliferation with aging [26,75]. Increased amyloid deposition is a characteristic of the aged arterial wall. A specific amyloid protein, known as medin, is deposited in the aortic media in the majority of Caucasians over 50 years of age. In addition, both med- in and MFG-E8, in an amyloid protein complex, bind to tropoelastin [76 78]. Thus, MFG-E8/medin amyloid may likely be a factor in the increased aortic stiffness that accompanies advancing age. Indeed, serum MFG-E8 levels and pulse wave velocity, an index of arterial stiffening, correlate with cardiovascular risk factors in old humans with type 2 diabetes [79]. 11 PROINFLAMMATORY MOLECULAR, CELLULAR, AND VASCULAR EVENTS IN THE AGING ARTERIAL WALL EARLY VASCULAR AGING (EVA)
- 24. Fibronectin In large arteries,the increase in α5β1 and fibronectin participates in the adaptation to mechanical stress in aged spontaneously hypertensive rats through increased numbers of cell matrix attachments and phenotypic changes [80]. Pressure and age induce accumulation of fibronectin and more specifically the EIIIA isoform [21]. Paralleling the increase in integrins in the aging vasculature are marked increases in fibronectin levels [73]. Inhibition of αvβ3 integrin increases senescence of SMCs [81], which suggests an up-regulation of this integrin with aging. Interestingly, the level of integrin β4 increases in the endothelium of mouse aorta with aging, which contributes to vascular EC senescence by affecting the levels of p53 and ROS [82]. TRANSCRIPTION FACTORS Cytoskeletal Serum Response Transcription Factor Serum response factor (SRF) (Figure 2.1) is a MADS (MCM1, Agamous, Deficiens, SRF) box transcription factor that regulates numerous cytoskeletal SMC genes, which produce SM-actin, SM-myosin heavy chain, calponin, troponin, dystrophin, and desmin through specific CArG-element-binding sites. SRF has also been implicated in EC migration during sprouting angiogenesis [83]. SRF is highly expressed in SMCs compared to most other tis- sues and appears to increase with aging (personal data) and in cerebral arteries of Alzheimer’s patients [84]. The development of hypertension in spontaneously hypertensive rats is also linked to an increased SRF-binding affin- ity to the CArG box present in the SM-myosin light-chain kinase promoter, resulting in higher phosphorylation of the myosin light chain [85]. VSMC phenotypic modifications are induced by SRF and control vascular tone as well as carotid stiffness via modulation of genes coding for components of the contractile apparatus and integrins without changes in collagen, elastin, fibronectin, and MMPs [86]. Proinflammatory Transcription Factors Ets-1 and NF-κB Pronflammatory transcription factors Ets-1 and nuclear factor kappaB (NF-κB) associated with Ang II signaling are both increased within the arterial wall with aging (Figure 2.1). Elevated Ets-1 activity is closely associated with increased transcription of ET-1, MCP-1, TGF-β1, and MMP-2 within the old arterial wall [44]. Activated NF- κB regulates the activity of MMP-2/-9, calpain-1, MCP-1, TGF-β1, and ROS, which deliver multiple signals and potentially drive arterial aging [7,87]. ANTI-INFLAMMATORY MOLECULE SIRT1 Sirtuins, including SIRT1, are members of a small family of enzymes that require nicotinamide adenine dinu- cleotide (NAD1 ) for their deacetylase or ADP-ribosyltransferase activity (Figure 2.1). The mRNA expression of the seven isoforms with unique subcellular localization and distinct functions in ECs is reduced with aging. SIRT1, located predominantly in the nucleus but also found in cytoplasm, is highly expressed in vascular ECs. Expression of SIRT1 is reduced in ECs from older versus younger mice and older versus younger healthy human adults. Decreases in arterial expression and activity of SIRT1 with advancing age are associated with increased acetylated eNOS, which inhibit eNOS activity and in turn contribute to vascular endothelial dysfunction [88]. The transcription factors p53, NF-κB, and forkhead box-containing protein type O subfamily (FOXO) have also been identified as deacetylation substrates of SIRT1, thereby down-regulating stress-induced premature senes- cence in ECs. SIRT1 also regulates oxidative stress at the chromatin level via decrease in acetylated histone H3 binding to the ShcA adapter protein P66Shc promoter region [89]. Recent reports have brought particular emphasis to the implication of sirtuins in healthy aging. Among the sir- tuins, SIRT1 has been the most extensively characterized for its protective role in aging and cardiovascular dis- eases, which depends upon the tissue and its degree of activation. Low to moderate over-expression of SIRT1 in mouse hearts reduces cardiac dysfunction and senescence markers, while high levels of SIRT1 expression are associated with cardiomyopathy and high levels of oxidative stress [90]. The protective role of SIRT1 is also related to its ability to decrease the age-associated impairment in endothelium-dependent dilatation without affecting endothelium-independent dilatation. Transfection of ApoE2/2 mice with a truncated inactive SIRT1 increases DNA damage, inflammation, and atherothrombotic lesions [91]. Inflammation and endothelial 12 2. CELLULAR AND MOLECULAR DETERMINANTS OF ARTERIAL AGING EARLY VASCULAR AGING (EVA)
- 25. dysfunction shift thehemostatic balance in favor of thrombosis in aging, and that in turn, can further enhance inflammation. Production and secretion of coagulation enzymes and cofactors as well as von Willebrand factor by vascular cells increase as the vascular wall function deteriorates with age [92]. In addition, the age-associated irreversible cellular senescence process, leading to a progressive decrease in plasticity and reprogramming potential of SMCs, plays a complementary signaling role and contributes to the increase in oxidation, fibrosis, calcification, and arterial stiffness [46,53,81]. CONCLUSION Several new altered molecular and cellular pathways in the aging arterial remodeling have emerged and prompted the development of selective drugs such as inhibitors of Ang II signaling or downstream molecules MMP, MCP-1, and TGF-β; integrin antagonists; and SIRT1 activators. 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[3] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:e28 e292. [4] Lloyd-Sherlock P, Beard J, Minicuci N, Ebrahim S, Chatterji S. Hypertension among older adults in low- and middle-income countries: prevalence, awareness and control. Int J Epidemiol 2014;43:116 28. [5] Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol 2009;8:345 54. [6] Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 2013;14:877 82. [7] Wang M, Jiang L, Monticone RE, Lakatta EG. Proinflammation: the key to arterial aging. Trends Endocrinol Metab 2014;25:72 9. [8] Wang M, Khazan B, Lakatta EG. Central arterial aging and angiotensin II signaling. Curr Hypertens Rev 2010;6:266 81. [9] Wang M, Monticone RE, Lakatta EG. Arterial aging: a journey into subclinical arterial disease. Curr Opin Nephrol Hypertens 2010;19:201 7. [10] Bochaton-Piallat ML, Gabbiani F, Ropraz P, Gabbiani G. Age influences the replicative activity and the differentiation features of cul- tured rat aortic smooth muscle cell populations and clones. Arterioscler Thromb 1993;13:1449 55. [11] Connat JL, Busseuil D, Gambert S, Ody M, Tebaldini M, Gamboni S, et al. Modification of the rat aortic wall during ageing; possible rela- tion with decrease of peptidergic innervation. Anat Embryol (Berl) 2001;204:455 68. [12] Li Z, Cheng H, Lederer WJ, Froehlich J, Lakatta EG. Enhanced proliferation and migration and altered cytoskeletal proteins in early pas- sage smooth muscle cells from young and old rat aortic explants. Exp Mol Pathol 1997;64:1 11. [13] Nikkari ST, Koistinaho J, Jaakkola O. Changes in the composition of cytoskeletal and cytocontractile proteins of rat aortic smooth muscle cells during aging. Differentiation 1990;44:216 21. [14] Qiu H, Zhu Y, Sun Z, Trzeciakowski JP, Gansner M, Depre C, et al. Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 2010;107:615 19. [15] Jiang L, Wang M, Zhang J, Monticone RE, Telljohann R, Spinetti G, et al. Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells. PLoS One 2008;3:e2231. [16] Ferlosio A, Arcuri G, Doldo E, Scioli MG, De Falco S, Spagnoli LG, et al. Age-related increase of stem marker expression influences vascular smooth muscle cell properties. Atherosclerosis 2012;224:51 7. [17] Blough ER, Rice KM, Desai DH, Wehner P, Wright GL. Aging alters mechanical and contractile properties of the Fisher 344/Nnia X Norway/Binia rat aorta. Biogerontology 2007;8:303 13. [18] Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R, et al. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 2007;50:219 27. [19] Shehadeh LA, Webster KA, Hare JM, Vazquez-Padron RI. Dynamic regulation of vascular myosin light chain (MYL9) with injury and aging. PLoS One 2011;6:e25855. 13 REFERENCES EARLY VASCULAR AGING (EVA)
- 26. Discovering Diverse ContentThrough Random Scribd Documents
- 30. The Project GutenbergeBook of The Vibration Wasps
- 31. This ebook isfor the use of anyone anywhere in the United States and most other parts of the world at no cost and with almost no restrictions whatsoever. You may copy it, give it away or re-use it under the terms of the Project Gutenberg License included with this ebook or online at www.gutenberg.org. If you are not located in the United States, you will have to check the laws of the country where you are located before using this eBook. Title: The Vibration Wasps Author: Frank Belknap Long Illustrator: John R. Forte Release date: March 15, 2021 [eBook #64820] Most recently updated: October 28, 2024 Language: English Credits: Greg Weeks, Mary Meehan and the Online Distributed Proofreading Team at http://www.pgdp.net *** START OF THE PROJECT GUTENBERG EBOOK THE VIBRATION WASPS ***
- 33.
- 34. by FRANK BELKNAPLONG Enormous, they were—like Jupiter—and unutterably terrifying to Joan— [Transcriber's Note: This etext was produced from Comet January 41. Extensive research did not uncover any evidence that the U.S. copyright on this publication was renewed.]
- 35. CHAPTER I OUT INSPACE I was out in space with Joan for the sixth time. It might as well have been the eighth or tenth. It went on and on. Every time I rebelled Joan would shrug and murmur: "All right, Richard. I'll go it alone then." Joan was a little chit of a girl with spun gold hair and eyes that misted when I spoke of Pluto and Uranus, and glowed like live coals when we were out in space together. Joan had about the worst case of exploritis in medical history. To explain her I had to take to theory. Simply to test out whether she could survive and reach maturity in an environment which was hostile to human mutants, Nature had inserted in her make-up every reckless ingredient imaginable. Luckily she had survived long enough to fall in love with sober and restraining me. We supplemented each other, and as I was ten years her senior my obligations had been clear-cut from the start. We were heading for Ganymede this time, the largest satellite of vast, mist-enshrouded Jupiter. Our slender space vessel was thrumming steadily through the dark interplanetary gulfs, its triple atomotors roaring. I knew that Joan would have preferred to penetrate the turbulent red mists of Ganymede's immense primary, and that only my settled conviction that Jupiter was a molten world restrained her. We had talked it over for months, weighing the opinions of Earth's foremost astronomers. No "watcher of the night skies" could tell us very much about Jupiter. The year 1973 had seen the exploration of the moon, and in 1986 the crews of three atomotor-propelled space vessels had landed on Mars and Venus, only to make the disappointing discovery that neither planet had ever sustained life.
- 36. By 2002 threeof the outer planets had come within the orbit of human exploration. There were Earth colonies on all of the Jovian moons now, with the exception of Ganymede. Eight exploring expeditions had set out for that huge and mysterious satellite, only to disappear without leaving a trace. I turned from a quartz port brimming with star-flecked blackness to gaze on my reckless, nineteen-year-old bride. Joan was so strong- willed and competent that it was difficult for me to realize she was scarcely more than a child. A veteran of the skyways, you'd have thought her, with her slim hands steady on the controls, her steely eyes probing space. "The more conservative astronomers have always been right," I said. "We knew almost as much about the moon back in the eighteenth century as we do now. We get daily weather reports from Tycho now, and there are fifty-six Earth colonies beneath the lunar Apennines. But the astronomers knew that the moon was a sterile, crater-pitted world a hundred years ago. They knew that there was no life or oxygen beneath its brittle stars generations before the first space vessel left Earth. "The astronomers said that Venus was a bleak, mist-enshrouded world that couldn't sustain life and they were right. They were right about Mars. Oh, sure, a few idle dreamers thought there might be life on Mars. But the more conservative astronomers stood pat, and denied that the seasonal changes could be ascribed to a low order of vegetative life. It's a far cry from mere soil discoloration caused by melting polar ice caps to the miracle of pulsing life. The first vessel to reach Mars proved the astronomers right. Now a few crack- brained theorists are trying to convince us that Jupiter may be a solid, cool world." Joan turned, and frowned at me. "You're letting a few clouds scare you, Richard," she said. "No man on Earth knows what's under the mist envelope of Jupiter."
- 37. "A few clouds,"I retorted. "You know darned well that Jupiter's gaseous envelope is forty thousand miles thick—a seething cauldron of heavy gases and pressure drifts rotating at variance with the planet's crust." "But Ganymede is mist-enshrouded too," scoffed Joan. "We're hurtling into that cauldron at the risk of our necks. Why not Jupiter instead?" "The law of averages," I said, "seasoned with a little common sense. Eight vessels went through Ganymede's ghost shroud into oblivion. There have been twenty-six attempts to conquer Jupiter. A little world cools and solidifies much more rapidly than a big world. You ought to know that." "But Ganymede isn't so little. You're forgetting it's the biggest satellite in the solar system." "But still little—smaller than Mars. Chances are it has a solid crust, like Callisto, Io, and Europa." There was a faint, rustling sound behind us. Joan and I swung about simultaneously, startled by what was obviously a space-code infraction. A silvery-haired, wiry little man was emerging through the beryllium steel door of the pilot chamber, his face set in grim lines. I am not a disciplinarian, but my nerves at that moment were strained to the breaking point. "What are you doing here, Dawson," I rapped, staring at him in indignation. "We didn't send for you." "Sorry, sir," the little man apologized. "I couldn't get you on the visi- plate. It's gone dead, sir." Joan drew in her breath sharply. "You mean there's something wrong with the cold current?" Dawson nodded. "Nearly every instrument on the ship has gone dead, sir. Gravity-stabilizers, direction gauges, even the intership communication coils." Joan leapt to her feet. "It must be the stupendous gravity tug of Jupiter," she exclaimed. "Hadley warned us it might impede the
- 38. molecular flow ofour cold force currents the instant we passed Ganymede's orbit." Exultation shone in her gaze. I stared at her, aghast. She was actually rejoicing that the Smithsonian physicist had predicted our destruction. Knowing that vessels were continually traveling to Io and Callisto despite their nearness to the greatest disturbing body in the Solar System, I had assumed we could reach Ganymede with our navigation instruments intact. I had scoffed at Hadley's forebodings, ignoring the fact that we were using cold force for the first time in an atomotor propelled vessel, and were dependent on a flow adjustment of the utmost delicacy. Dawson was staring at Joan in stunned horror. Our fate was sealed and yet Joan had descended from the pilot dais and was actually waltzing about the chamber, her eyes glowing like incandescent meteor chips. "We'll find out now, Richard," she exclaimed. "It's too late for caution or regrets. We're going right through forty thousand miles of mist to Jupiter's solid crust." CHAPTER II THROUGH THE CLOUD BLANKET I thought of Earth as we fell. Tingling song, and bright awakenings and laughter and joy and grief. Woodsmoke in October, tall ships and the planets spinning and hurdy-gurdies in June. I sat grimly by Joan's side on the pilot dais, setting my teeth as I gripped the atomotor controls and stared out through the quartz port. We were plummeting downward with dizzying speed. Outside the quartz port there was a continuous misty glimmering splotched with nebulously weaving spirals of flame.
- 39. We were alreadyfar below Jupiter's outer envelope of tenuous gases in turbulent flux, and had entered a region of pressure drifts which caused our little vessel to twist and lunge erratically. Wildly it swept from side to side, its gyrations increasing in violence as I cut the atomotor blasts and released a traveling force field of repulsive negrations. I thanked our lucky stars that the gravity tug had spared the atomotors and the landing mechanism. We hadn't anything else to be thankful for. I knew that if we plunged into a lake of fire even the cushioning force field couldn't save us. Joan seemed not to care. She was staring through the quartz port in an attitude of intense absorption, a faint smile on her lips. There are degrees of recklessness verging on insanity; of courage which deserves no respect. I had an impulse to shake her, and shout: "Do you realize we're plunging to our death?" I had to keep telling myself that she was still a child with no realization of what death meant. She simply couldn't visualize extinction; the dreadful blackness sweeping in— Our speed was decreasing now. The cushioning force field was slowing us up, forcing the velocity needle sharply downward on the dial. Joan swung toward me, her face jubilant. "We'll know in a minute, Richard. We're only eight thousand miles above the planet's crust." "Crust?" I flung at her. "You mean a roaring furnace." "No, Richard. If Jupiter were molten we'd be feeling it now. The plates would be white-hot." It was true, of course. I hadn't realized it before. I wiped sweat from my forehead, and stared at her with sombre respect. She had been right for once. In her girlish folly she had out-guessed all the astronomers on Earth. The deceleration was making my temples throb horribly. We were decelerating far too rapidly, but it was impossible to diminish the
- 40. speed-retarding pressure ofthe force field, and I didn't dare resort to another atomotor charge so close to the planet's surface. To make matters worse, the auxiliary luminalis blast tubes had been crippled by the arrest of the force current, along with the almost indispensable gravity stabilizers. The blood was draining from my brain already. I knew that I was going to lose consciousness, and my fingers passed swiftly up and down the control panel, freezing the few descent mechanisms which were not dependent on the interior force current in positions of stability and maximum effectiveness, and cupping over the meteor collision emergency jets. Joan was the first to collapse. She had been quietly assisting me, her slim hands hovering over the base of the instrument board. Suddenly as we manipulated dials and rheostats she gave a little, choking cry and slumped heavily against me. There was a sudden increase of tension inside my skull. Pain stabbed at my temples and the control panel seemed to waver and recede. I threw my right arm about Joan and tried to prevent her sagging body from slipping to the floor. A low, vibrant hum filled the chamber. We rocked back and forth before the instrument board, our shoulders drooping. We were still rocking when a terrific concussion shook the ship, hurling us from the dais and plunging the chamber into darkness. Bruised and dazed, I raised myself on one elbow and stared about me. The jarred fluorescent cubes had begun to function again, filling the pilot chamber with a slightly diminished radiance. But the chamber was in a state of chaos. Twisted coils of erillium piping lay at my feet, and an overturned jar of sluice lubricant was spilling its sticky contents over the corrugated metal floor. Joan had fallen from the pilot dais and was lying on her side by the quartz port, her face ashen, blood trickling from a wound in her cheek. I pulled myself toward her, and lifted her up till her shoulders
- 41. were resting onmy knees. Slowly her eyes blinked open, and bored into mine. She forced a smile. "Happy landing?" she inquired. "Not so happy," I muttered grimly. "You were right about Jupiter. It's a solid world and we've landed smack upon it with considerable violence, judging from the way things have been hurled about." "Then the cushioning force field—" "Oh, it cushioned us, all right. If it hadn't we'd be roasting merrily inside a twisted mass of wreckage. But I wouldn't call it happy landing. You've got a nasty cut there." "I'm all right, Richard." Joan reached up and patted my cheek. "Good old Richard. You're just upset because we didn't plunge into a lake of molten zinc." "Sure, that's it," I grunted. "I was hoping for a swift, easy out." "Maybe we'll find it, Richard," she said, her eyes suddenly serious. "I'm not kidding myself. I know what a whiff of absolute zero can do to mucous membranes. All I'm claiming is that we've as good a chance here as we would have had on Ganymede." "I wish I could feel that way about it. How do we know the atomotors can lift us from a world as massive as Jupiter?" "I think they can, Richard. We had twelve times as much acceleration as we needed on tap when we took off from Earth." She was getting to her feet now. Her eyes were shining again, exultantly. You would have thought we were descending in a stratoplane above the green fields of Earth. "I've a confession to make, Richard," she grinned. "Coming down, I was inwardly afraid we would find ourselves in a ghastly bubble and boil. And I was seriously wondering how long we could stand it." "Oh, you were."
- 42. "Longer than youthink, Richard. Did you know that human beings can stand simply terrific heat? Experimenters have stayed in rooms artificially heated to a temperature of four hundred degrees for as long as fifteen minutes without being injured in any way." "Very interesting," I said. "But that doesn't concern us now. We've got to find out if our crewmen are injured or badly shaken up. Chances are they'll be needing splints. And we've got to check the atmosphere before we can think of going outside, even with our helmets clamped down tight. "Chances are it's laden with poisonous gases which the activated carbon in our oxygen filters won't absorb. If the atmosphere contains phosgene we'll not be stepping out. I'm hoping we'll find only carbon monoxide and methane." "Nice, harmless gases." "I didn't say that. But at least they'll stick to the outside of the particles of carbon in the filter and not tear our lungs apart." "A thought, Richard. Suppose we find nickel carbonyl. That's harmless until it is catalyzed by carbon. Then it's worse than phosgene." "There are lots of deadly ingredients we could find," I admitted with some bitterness. "Gases in solid toxic form—tiny dust granules which would pass right through the filters into our lungs. Jupiter's atmosphere may well be composed entirely of gases in solid phase." "Let's hope not, Richard." "We've been talking about lung corrosives," I said, relentlessly. "But our space suits are not impermeable, you know. There are gases which injure the skin, causing running sores. Vesicant gases. The fact that there are no vesicants on Io and Europa doesn't mean we won't encounter them here. And there are nerve gases which could drive us mad in less time than it takes to—" "Richard, you always were an optimist."
- 43. I stared ather steadily for an instant; then shrugged. "All right, Joan. I hope you won't fall down on any of the tests. We've got to project an ion detector, a barometer and a moist cloud chamber outside the ship through a vacuum suction lock, in addition to the atmosphere samplers. And we've got to bandage that face wound before you bleed to death." CHAPTER III WHAT THE CAMERA SHOWED A half hour later we had our recordings. Joan sat facing me on the elevated pilot dais, her head swathed in bandages. Dawson and the two other members of our crew stood just beneath us, their faces sombre in the cube-light. They had miraculously escaped injury, although Dawson had a badly shaken up look. His hair was tousled and his jaw muscles twitched. Dawson was fifty-three years old, but the others were still in their early twenties—stout lads who could take it. The fuel unit control pilot, James Darnel, was standing with his shoulders squared, as though awaiting orders. I didn't want to take off. I had fought Joan all the way, but now that we were actually on Jupiter I wanted to go out with her into the unknown, and stand with her under the swirling, star-concealing mist. I wanted to be the first man to set foot on Jupiter. But I knew now that the first man would be the last. The atmospheric recordings had revealed that there were poisons in Jupiter's lethal cloud envelope which would have corroded our flesh through our space suits and burned out our eyes. Joan had been compelled to bow to the inevitable. Bitterly she sat waiting for me to give the word to take off. I was holding a portable horizon camera in my hand. It was about the smallest, most incidental article of equipment we had brought along.
- 44. The huge, electro-shutteredhorizon camera which we had intended to use on Ganymede had been so badly damaged by the jar of our descent that it was useless now. We had projected the little camera by a horizontal extension tripod through a vacuum suction lock and let it swing about. I didn't expect much from it. It was equipped with infra-red and ultra-violet ray filters, but the atmosphere was so dense outside I didn't think the sensitive plates would depict anything but swirling spirals of mist. I was waiting for the developing fluid to do its work before I broke the camera open and removed the plates. We had perhaps one chance in ten of getting a pictorial record of Jupiter's topographical features. I knew that one clear print would ease Joan's frustration and bitterness, and give her a sense of accomplishment. But I didn't expect anything sensational. Venus is a frozen wasteland from pole to pole, and the dust-bowl deserts of Mars are exactly like the more arid landscapes of Earth. Most of Earth is sea and desert and I felt sure that Jupiter would exhibit uniform surface features over nine-tenths of its crust. Its rugged or picturesque regions would be dispersed amidst vast, dun wastes. The law of averages was dead against our having landed on the rim of some blue-lit, mysterious cavern measureless to man, or by the shores of an inland sea. But Joan's eyes were shining again, so I didn't voice my misgivings. Joan's eyes were fastened on the little camera as though all her life were centered there. "Well, Richard," she urged. My hands were shaking. "A few pictures won't give me a lift," I said. "Even if they show mountains and crater-pits and five hundred million people gape at them on Earth."
- 45. "Don't be sucha pessimist, Richard. We'll be back in a month with impermeable space suits, and a helmet filter of the Silo type. You're forgetting we've accomplished a lot. It's something to know that the temperature outside isn't anything like as ghastly as the cold of space, and that the pebbles we've siphoned up show Widman- statten lines and contain microscopic diamonds. That means Jupiter's crust isn't all volcanic ash. There'll be something more interesting than tumbled mounds of lava awaiting us when we come back. If we can back our geological findings with prints—" "You bet we can," I scoffed. "I haven't a doubt of it. What do you want to see? Flame-tongued flowers or gyroscopic porcupines? Take your choice. Richard the Great never fails." "Richard, you're talking like that to hide something inside you that's all wonder and surmise." Scowling, I broke open the camera and the plates fell out into my hand. They were small three by four inch positive transparencies, coated on one side with a iridescent emulsion which was still slightly damp. Joan's eyes were riveted on my face. She seemed unaware of the presence of the crewmen below us. She sat calmly watching me as I picked up the top-most plate and held it up in the cube-light. I stared at it intently. It depicted—a spiral of mist. Simply that, and nothing more. The spiral hung in blackness like a wisp of smoke, tapering from a narrow base. "Well?" said Joan. "Nothing on this one," I said, and picked up another. The spiral was still there, but behind it was something that looked like an ant-hill. "Thick mist getting thinner," I said. The third plate gave me a jolt. The spiral had become a weaving ghost shroud above a distinct elevation that could have been either a mountain or an ant-hill. It would have been impossible to even
- 46. guess at theelevation's distance from the ship if something hadn't seemed to be crouching upon it. The mist coiled down over the thing and partly obscured it. But enough of it was visible to startle me profoundly. It seemed to be crouching on the summit of the elevation, a wasplike thing with wiry legs and gauzy wings standing straight out from its body. My fingers were trembling so I nearly dropped the fourth plate. On the fourth plate the thing was clearly visible. The spiral was a dispersing ribbon of mist high up on the plate and the mound was etched in sharp outlines on the emulsion. The crouching shape was unmistakably wasplike. It stood poised on the edge of the mound, its wings a vibrating blur against the amorphously swirling mist. From within the mound a companion shape was emerging. The second "wasp" was similar to the poised creature in all respects, but its wings did not appear to be vibrating and from its curving mouth- parts there dangled threadlike filaments of some whitish substance which was faintly discernible against the mist. The fifth and last plate showed both creatures poised as though for flight, while something that looked like the head of still another wasp was protruding from the summit of the mound. I passed the plates to Joan without comment. Wonder and exaltation came into her face as she examined them, first in sequence and then haphazardly, as though unable to believe her eyes. "Life," she murmured at last, her voice tremulous with awe. "Life on Jupiter. Richard, it's—unbelievable. This great planet that we thought was a seething cauldron is actually inhabited by—insects." "I don't think they're insects, Joan," I said. "We've got to suspend judgment until we can secure a specimen and study it at close range. It's an obligation we owe to our sponsors and—to ourselves. We're here on a mission of scientific exploration. We didn't inveigle
- 47. funds from theSmithsonian so that we could rush to snap conclusions five hundred million miles from Earth. "Insectlike would be a safer word. I've always believed that life would evolve along parallel lines throughout the entire solar system, assuming that it could exist at all on Venus, Mars, or on one of the outer planets. I've always believed that any life sustaining environment would produce forms familiar to us. On Earth you have the same adaptations occurring again and again in widely divergent species. "There are lizards that resemble fish and fish that are lizardlike. The dinosaur Triceratops resembled a rhinoceros, the duck-billed platypus a colossal. Porpoises and whales are so fishlike that no visitor from space would ever suspect that they were mammals wearing evolutionary grease paint. And some of the insects look just like crustaceans, as you know. "These creatures look like insects, but they may not even be protoplasmic in structure. They may be composed of some energy- absorbing mineral that has acquired the properties of life." Joan's eyes were shining. "I don't care what they're composed of, Richard. We've got to capture one of those creatures alive." I shook my head. "Impossible, Joan. If the air outside wasn't poisonous I'd be out there with a net. But there are limits to what we can hope to accomplish on this trip." "We've siphoned up specimens of the soil," Joan protested. "What's to stop us from trying to catch up one of them in a suction cup?" "You're forgetting that suction cups have a diameter of scarcely nine inches," I said. "These creatures may be as huge as the dragonflies of the Carboniferous Age." "Richard, we'll project a traveling suction cup through one of the vacuum locks and try to—" Her teeth came together with a little click. Startled, I turned and stared at her. Despite her elation she had been sitting in a relaxed
- 48. attitude, with herback to the control panel and her latex taped legs extended out over the dais. Now she was sitting up straight, her face deathly pale in the cube-light. The creatures were standing a little to the right of the rigidly staring crewmen, their swiftly vibrating wings enveloped in a pale bluish radiance which swirled upward toward the ribbed metal ceiling of the pilot chamber. The creature was standing, wings swiftly vibrating, enveloped in a pale, bluish radiance.
- 49. Enormous they were—andunutterably terrifying with their great, many-faceted eyes fastened in brooding malignance upon us. Joan and I arose simultaneously, drawn to our feet by a horror such as we had never known. A sense of sickening unreality gripped me, so that I could neither move nor cry out. Dawson alone remained articulate. He raised his arm and pointed, his voice a shrill bleat. "Look out, sir! Look out! There's another one coming through the wall directly behind you." The warning came too late. As I swung toward the quartz port I saw Joan's arm go out, her body quiver. Towering above her was a third gigantic shape, the tip of its abdomen resting on her shoulders, its spindly legs spread out over the pilot dais. As I stared at it aghast it shifted its bulk, and a darkly gleaming object that looked like a shrunken bean-pod emerged from between Joan's shoulder blades. Joan moaned and sagged on the dais, her hands going to her throat. Instantly the wasp swooped over me, its abdomen descending. For an awful instant I could see only a blurred shapelessness hovering over me. Then a white-hot shaft of pain lanced through me and the blur receded. But I was unable to get up. I was unable to move or think clearly. My limbs seemed weighted. I couldn't get up or help Joan or even roll over. My head was bursting and my spine was a board. I must have tried to summon help, for I seem to remember Dawson sobbing: "I'm paralyzed too, sir," just before my senses left me and I slumped unconscious on the dais. How long I remained in blackness I had no way of knowing. But when I opened my eyes again I was no longer on the dais. I was up under the ceiling of the pilot chamber, staring down at the
- 50. corrugated floor throughwhat looked like a glimmering, whitish haze. Something white and translucent wavered between my vision and the floor, obscuring the outlines of the great wasps standing there. There were five wasps standing directly beneath me in the center of the pilot chamber, their wings a luminous blur in the cube-light. My perceptions were surprisingly acute. I wasn't confused mentally, although my mouth felt parched and there was a dull, throbbing ache in my temples. The position in which I found myself and the whitish haze bewildered me for only an instant. I knew that the "haze" was a web the instant I studied its texture. And when I tried to move and couldn't the truth dawned in all its horror. I was suspended beneath the ceiling of the chamber in a translucent, hammock-like web. I was lying on my stomach, my limbs bound by fibrous strands as resistant as whipcords. Minutes which seemed like eternities passed as I lay there with fear clutching at my heart. I could only gaze downward. The crewmen had vanished and the wasps were standing like grim sentinels in front of the control panel. I was almost sure that Joan and the crewmen were suspended in similar webs close to me. I thought I knew what the wasps had done to us. I had talked to Joan about life evolving along parallel lines throughout the Solar System, but I hadn't expected to encounter life as strange and frightening as this—insectlike, and yet composed of some radiant substance that could penetrate solid metal and flow at will through the walls of a ship. Some radiant substance that had weight and substance and could touch human flesh without searing it. Nothing so ghastly strange and yet—indisputably the creatures were wasplike. And being
- 51. wasplike their habitpatterns were similar to those of so-called social wasps on Earth. Social wasps sting caterpillars into insensibility, and deposit eggs in their paralyzed flesh. When the wasp-grubs hatch they become ghoulish parasites, gruesomely feasting until the caterpillars dwindle to repulsive, desiccated husks. CHAPTER IV EDDINGTON'S OSCILLATIONS Horror and sick revulsion came into me as I stared down at the great wasps, with their many-faceted eyes seeming to probe the Jovian mists through a solid metal bulkhead! They thought we were Jovian caterpillars! Evidently there were flabby, white larva-shapes out in the mist as large as men—with the habit perhaps of rearing upright on stumpy legs like terrestrial measuring worms. We looked enough like Jovian caterpillars to deceive those Jovian wasps. They had apparently seen us through the walls of the ship, and their egg-laying instincts had gone awry. They had plunged ovipositors into our flesh, spun webs about us and hung us up to dry out while their loathsome progeny feasted on our flesh. The whitish substance exuding from the mouth-parts of one of the photographed wasps had evidently been mucilaginous web material. There was no other possible explanation. And suddenly as I lay there with thudding temples something occurred which increased my horror ten-fold. Zigzagging, luminous lines appeared on the ribbed metal wall opposite the quartz port and a wasp materialized amidst spectral bands of radiance which wavered and shimmered like heat waves in bright sunlight.
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