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Early‐Life Programming of Aging and Longevity: The Idea of High Initial Damage Load (the HIDL Hypothesis)

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Leonid A. Gavrilov at University of Chicago
Leonid A. Gavrilov
Natalia Gavrilova at University of Chicago
Natalia Gavrilova
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In this study, we test the predictions of the high initial damage load (HIDL) hypothesis, a scientific idea that early development of living organisms produces an exceptionally high load of initial damage, which is comparable with the amount of subsequent aging-related deterioration accumulating during the rest of the entire adult life. This hypothesis predicts that even small progress in optimizing the early-developmental processes can potentially result in a remarkable prevention of many diseases in later life, postponement of aging-related morbidity and mortality, and significant extension of healthy life span.
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1
Ann. N.Y. Acad. Sci. 1019: 1–6 (2004). © 2004 New York Academy of Sciences.
doi: 10.1196/annals.1297.091
Early-Life Programming of Aging
and Longevity
The Idea of High Initial Damage Load
(the HIDL Hypothesis)
LEONID A. GAVRILOV AND NATALIA S. GAVRILOVA
Center on Aging, National Opinion Research Center (NORC) and University of Chicago,
Chicago, Illinois 60637, USA
ABSTRACT: In this study, we test the predictions of the high initial damage load
(HIDL) hypothesis, a scientific idea that early development of living organisms
produces an exceptionally high load of initial damage, which is comparable
with the amount of subsequent aging-related deterioration accumulating during
the rest of the entire adult life. This hypothesis predicts that even a small
progress in optimizing the early-developmental processes can potentially result
in a remarkable prevention of many diseases in later life, postponement of aging-
related morbidity and mortality, and significant extension of healthy life span.
KEYWORDS: high initial damage load (HIDL); aging; longevity; early-life;
development; programming
INTRODUCTION
In 1991, we suggested a scientific idea that early development of living organisms
produces an exceptionally high load of initial damage, which is comparable with the
amount of subsequent aging-related deterioration accumulating during the rest of the
entire adult life.1
This idea of high initial damage load (the HIDL hypothesis) predicts that even a
small progress in optimizing the early-developmental processes can potentially result
in a remarkable prevention of many diseases in later life, postponement of aging-
related morbidity and mortality, and significant extension of healthy life span.1–3
Thus, the idea of early-life programming of aging and longevity may have important
practical implications for developing early-life interventions promoting health and
longevity.
In this study, we tested the predictions of the HIDL hypothesis. Specifically, the
HIDL hypothesis predicts that early-life events may affect survival in later adult life
through the level of initial damage. This prediction is confirmed for such early-life
factors as paternal age at a person’s conception4 and the month of a person’s birth.4,5
Address for correspondence: Leonid A. Gavrilov, Center on Aging, NORC/University of Chicago,
1155 East 60th Street, Chicago, IL 60637-2745. Voice: 773-256-6359; fax: 773-256-6313.
gavrilov@longevity-science.org
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Forthcoming in the Annals of the New York Academy of Sciences, vol. 
1019, June 2004
2 ANNALS NEW YORK ACADEMY OF SCIENCES
Another testable prediction of the HIDL hypothesis is a prevision of an unusual
nonlinear pattern of life-span inheritance. This prediction is tested and confirmed:
familial transmission of life span from parents to children follows a nonlinear
(accelerating) pattern, with steeper slopes for offspring life span of longer-lived
parents, as predicted.6
DISCUSSION OF THE IDEA OF HIGH INITIAL DAMAGE LOAD
The introductory section presented earlier is written as an abstract briefly
summarizing the main ideas, findings, and conclusions of our studies. The purpose
of this section is to provide a more detailed discussion of the idea of HIDL.
Reliability theory of aging predicts that a failure rate of simple redundant systems
increases with age according to the Weibull (power) law.1–3 This theoretical predic-
tion is consistent with empirical observations that failure kinetics of technical devices
follow the Weibull law.7 However, biological systems “prefer” to fail according to
the Gompertz (exponential) law,1,8 which calls for explanations.
An attempt to explain exponential deterioration of biosystems in terms of the
reliability theory led us to a paradoxical conjecture that biological systems start their
adult life with a high load of initial damage.1–3
Although this idea may look like a counterintuitive assumption, it fits well with
many empirical observations on massive cell losses in early development. For
example, the female human fetus at 4–5 months of age possesses 6–7 million eggs
(oocytes). By birth, this number drops to 1–2 million and declines even further. At the
start of puberty in normal girls, there are only 0.3–0.5 million eggs, just only 4–8%
of initial numbers (for review, see Ref. 3).
Massive cell losses in early development are creating conditions for a Poisson
distribution of organisms according to the numbers of remaining cells, which in turn
produce the exponential (Gompertzian) law of mortality increase.1 Because the
mathematical proof for this statement is already published elsewhere for a more
general case of binomial distribution,1 we can concentrate here on substantive
discussion of the idea of HIDL in biological systems.
Biological systems are different from technical devices in two aspects. The first
fundamental feature of biosystems is that, in contrast to technical (artificial) devices,
which are constructed out of previously manufactured and tested components,
organisms form themselves in ontogenesis through a process of self-assembly out of
de novo forming and externally untested elements (cells). The second property of
organisms is the extraordinary degree of miniaturization of their components (the
microscopic dimensions of cells, as well as the molecular dimensions of information
carriers like DNA and RNA), permitting the creation of a huge redundancy in the
number of elements. Thus, we can expect that for living organisms, in distinction to
many technical (manufactured) devices, the reliability of the system is achieved not by
the high initial quality of all the elements, but by their huge numbers (redundancy).
The fundamental difference in the manner in which the system is formed (external
assembly in the case of technical devices and self-assembly in the case of bio-
systems) has two important consequences. First, it leads to the macroscopicity of
technical devices in comparison with biosystems since technical devices are assem-
bled “top-down” with the participation of a macroscopic system (humans) and must
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3GAVRILOV & GAVRILOVA: EARLY-LIFE PROGRAMMING OF AGING
be suitable for this macroscopic system to use (i.e., commensurate with humans).
Organisms, on the other hand, are assembled “bottom-up” from molecules and cells,
resulting in an exceptionally high degree of miniaturization of the component parts.
Second, since technical devices are assembled under the control of humans, the
opportunities to pretest components (external quality control) are incomparably
greater than in the self-assembly of biosystems. The latter inevitably leads to
organisms being “littered” with a great number of defective elements. As a result,
the reliability of technical devices is assured by the high quality of elements, with a
strict limit on their numbers because of size and cost limitations, while the reliability
of biosystems is assured by an exceptionally high degree of redundancy to overcome
the poor quality of some elements.
It follows from this concept of HIDL that even small progress in optimizing the
processes of ontogenesis and increasing the numbers of initially functional elements
can potentially result in a remarkable fall in mortality and a significant improvement
in life span. This optimistic prediction is supported by experimental evidence of
increased offspring life span in response to protection of parental germ cells against
oxidative damage just by feeding the future parents with antioxidants.9 Increased life
span is also observed among the progeny of parents with a low resting respiration
rate (proxy for the rate of oxidative damage to DNA of germ cells; see Ref. 1). The
concept of HIDL also predicts that early life events may affect survival in later adult
life through the level of initial damage. This prediction proved to be correct for such
early-life indicators as parental age at a person’s conception4 and the month of a
person’s birth (see FIG. 1, TABLE 1, and earlier publications4,5).
FIGURE 1. Daughters’ life span as a function of paternal age at daughter’s birth: 5063
daughters from European aristocratic families born in 1800–1880. Both parents lived 50+
years. Details of data analysis are described elsewhere.4
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4 ANNALS NEW YORK ACADEMY OF SCIENCES
Women may be particularly sensitive to early-life exposures because they are
mosaics of two different cell types (one with an active paternal X chromosome and
another one with an active maternal X chromosome). The exact pattern of this
mosaic is determined early in life. If early-life conditions affect the proportion (or
distribution pattern) of cells with a given X chromosome, such conditions might
have long-lasting effects in later life. Indeed, this conjecture of stronger female
response to early-life exposures is confirmed for such early-life predictors of adult life
span as paternal age at a person’s conception4 and the month of a person’s birth.4,5
Another testable prediction of the HIDL hypothesis is a prediction of an unusual
nonlinear pattern of life-span inheritance. Traditionally, it is assumed that the depen-
dence of progeny life span on parental life span should follow a linear relationship,
which is common to all other quantitative traits in classic quantitative genetics.10 In
other words, for each additional year of parental life span, the children are expected
to have some fixed gain in their average life span too, as a result of polygenic
TABLE 1. Female life span as a function of month of birth
Month of birth
Net effect, in years
(point estimate) Standard error P value
February 0.00 Reference level
March 1.10 0.92 .2331
April 1.72 0.92 .0619
May 2.35 0.90 .0090
June 1.66 0.90 .0665
July 1.86 0.91 .0404
August 1.49 0.90 .0978
September 1.51 0.92 .0986
October 1.95 0.90 .0308
November 2.13 0.93 .0229
December 3.04 0.91 .0009
January 0.94 0.92 .3086
February 0.00 Reference level
NOTE: Results are obtained through multivariate regression analysis of life-span data (outcome
variable) for 6908 women born in 1800–1880 (extinct birth cohorts with life span known for
each person), who survived by age 30 (focus on analysis of adult life span). The following addi-
tional predictor variables are also included in the final model because of their predictive value:
(1) calendar year of birth, (2) ethnicity (Russian, British, and others), (3) loss of father during
formative years of childhood (before age 15), (4) loss of mother during formative years of child-
hood (before age 15), (5) cause of death (violent vs. nonviolent), (6) early death of at least one
sibling (before age 30), (7) high birth order (7+), (8) nobility rank of the father (indicator of
social status), (9) large family size (number of siblings: 9+), (10) maternal life span, (11) paternal
life span, (12) paternal age at person’s birth, (13) late paternal age at first childbirth (50+ years),
(14) birth of the first child by mother after age 30, and (15) death of mother from violent cause of
death. The F value for the regression model is 18.12 (P < .0001). “Net effect” corresponds to
additional years of life gained (or lost) compared to the reference category (life span for those
born in February).
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5GAVRILOV & GAVRILOVA: EARLY-LIFE PROGRAMMING OF AGING
inheritance of quantitative traits.10 However, the HIDL hypothesis leads to a very
different prediction of a nonlinear (accelerated) “concave-up” pattern of life-span
inheritance. There should be virtually no life-span heritability (a negligible response
of progeny life span to the changes in parental life span) when parental life span is
below a certain age, and a much higher heritability (an increased response to parental
life span) when parents live longer lives. This prediction follows from the hypothesis
of HIDL among short-lived parents, whose bodies are damaged during early devel-
opmental processes, although their germ-cell DNA might be perfectly normal. (If the
germ-cell DNA were damaged too, these short-lived parents would probably
produce offspring who also live short lives. This category will thus be unlikely to
distort the linear dependence of offspring life span on parental life span by a large
amount.) Therefore, the progeny of some short-lived parents may have quite normal
life spans, well beyond genetic expectations. This result would thus obstruct the classic
linear offspring-on-parent dependence for life span. Only at some high parental life
span, when most of the germ-normal/somatically damaged parents are eliminated
because of their shorter length of life, will the classic linear pattern of life-span
inheritance eventually reveal itself in its full capacity. This prediction of the HIDL
hypothesis was tested and confirmed in humans: familial transmission of life span
from parents to children proved to follow a nonlinear (accelerating) pattern, with
steeper slopes for the life span of offspring born to longer-lived parents, as predicted.6
Thus, there is mounting evidence now in support of the idea of fetal origins of
adult degenerative diseases, and early-life programming of aging and longevity.4
ACKNOWLEDGMENTS
This study was made possible thanks to a generous support from the National
Institute on Aging (NIH) and a stimulating working environment at the Center on
Aging, NORC/University of Chicago. We would like to thank members of the
Science Advisory Board (SAB) (http://www.scienceboard.net/) for useful comments
on our work made at the SAB discussion group.
REFERENCES
1. GAVRIL OV, L.A. & N.S. GAVRILOVA. 1991. The Biology of Life Span: A Quantitative
Approach. Harwood Academic. New York.
2. GAVRILOV, L.A. & N.S. GAVRILOVA. 2001. The reliability theory of aging and longevity.
J. Theor. Biol. 213: 527–545.
3. GAVRIL OV, L.A. & N.S. GAVRI LOVA. 2003 (July 16). The quest for a general theory of
aging and longevity. Science’s SAGE KE (Science of Aging Knowledge Environment)
2003(28): 1–10 [available at http://sageke.sciencemag.org].
4. GAVRIL OV, L.A. & N.S. GAVR ILOVA. 2003. Early-life factors modulating lifespan.
In Modulating Aging and Longevity, pp. 27–50. Kluwer. Dordrecht.
5. GAVRIL OV, L.A. & N.S. GAVRILOVA. 1999. Season of birth and human longevity. J.
Anti-Aging Med. 2: 365–366.
6. GAVRIL OVA, N.S. & L.A. GAVRILOV. 2001. When does human longevity start?
Demarcation of the boundaries for human longevity. J. Anti-Aging Med. 4: 115–124.
7. WEIBULL, W.A. 1951. A statistical distribution function of wide applicability. J. Appl.
Mech. 18: 293–297.
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6 ANNALS NEW YORK ACADEMY OF SCIENCES
8. GOMPERTZ, B. 1825. On the nature of the function expressive of the law of human
mortality and on a new mode of determining life contingencies. Philos. Trans. R.
Soc. London A115: 513–585.
9. HARMAN, D. & D.E. EDDY. 1979. Free radical theory of aging: beneficial effects of
adding antioxidants to the maternal mouse diet on life span of offspring: possible
explanation of the sex difference in longevity. AGE 2: 109-122.
10. FALCONER, D.S. & T.F.C. MACKAY. 1996. Introduction to Quantitative Genetics.
Longman. London.
neg091gav.fm Page 6 Tuesday, March 30, 2004 9:29 AM
... epigenetic aging j fetal programming j Great Depression j aging Aging is characterized by the gradual accumulation of cellular damage, leading to physiological deterioration, loss of function, and increased vulnerability to death (1). A growing body of research suggests that the beginnings of human aging occur during the initial phases of embryogenesis, a paradigm shift in aging research that anchors the onset of age-related damage accumulation to the prenatal period as opposed to later in the life course after the completion of development and the onset of reproductive age (2,3). The idea that aging later in life could be linked to in utero programming has important implications for the development of early-life interventions that could postpone age-related morbidity and mortality and significantly extend healthy life span (2). ...
... A growing body of research suggests that the beginnings of human aging occur during the initial phases of embryogenesis, a paradigm shift in aging research that anchors the onset of age-related damage accumulation to the prenatal period as opposed to later in the life course after the completion of development and the onset of reproductive age (2,3). The idea that aging later in life could be linked to in utero programming has important implications for the development of early-life interventions that could postpone age-related morbidity and mortality and significantly extend healthy life span (2). ...
... Overall, it is difficult to disentangle whether the connection between in utero exposures and accelerated biological aging later in life that we observe is operating from epigenetic alterations induced during early development that result in consistently higher incidence of damage throughout life (i.e., fetal programming) (4,5) or epigenetic signs of aging processes that are accelerated by insults in utero but that continue to develop across the life course (i.e., the idea of high initial damage load or the HIDL hypothesis) (2). In both cases, any downstream consequences of early-life insults will not be readily apparent until we can observe aging at a phenotypic level when progressive accumulation of damage and loss of physiological integrity begin to take hold later in life. ...
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Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the US Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in state environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the preconception, postnatal, childhood, or early adolescent periods. After evaluating endogenous shifts in mortality and fertility related to Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.
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... Aging is characterized by the gradual accumulation of cellular damage, leading to physiological deterioration, loss of function, and increased vulnerability to death (1). A growing body of research suggests that the beginnings of human aging occur during the initial phases of embryogenesis-a paradigm shift in aging research that anchors the onset of age-related damage accumulation to the prenatal period as opposed to later in the life course after the completion of development and the onset of reproductive age (2,3). The idea that aging later in life could be linked to in utero programming has important implications for the development of early-life interventions that could postpone age-related morbidity and mortality and significantly extend healthy life span (2). ...
... A growing body of research suggests that the beginnings of human aging occur during the initial phases of embryogenesis-a paradigm shift in aging research that anchors the onset of age-related damage accumulation to the prenatal period as opposed to later in the life course after the completion of development and the onset of reproductive age (2,3). The idea that aging later in life could be linked to in utero programming has important implications for the development of early-life interventions that could postpone age-related morbidity and mortality and significantly extend healthy life span (2). ...
... The copyright holder for this preprint this version posted May 21, 2022. ; https://doi.org/10.1101/2022.05.18.22275258 doi: medRxiv preprint accelerated by insults in utero but that continue to develop across the life course (i.e., the idea of high initial damage load or the HIDL hypothesis) (2). In both cases, any downstream consequences of early-life insults will not be readily apparent until we can observe aging at a phenotypic level when progressive accumulation of damage and loss of physiological integrity begin to take hold later in life. ...
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Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the U.S. Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the pre-conception, postnatal, childhood, or early adolescent periods. After evaluating changes in mortality rates for Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.
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... Consequently, an individual can 'acquire' any number of phenotypes, often with long-term consequences for performance (Gilbert 2001). Developmental adaptation to a spectrum of adverse environmental conditions leads to increased susceptibility to diseases later in life (Barker 2004;Bateson et al. 2004;Gluckman et al. 2005;Vaiserman 2011a), and a significant relationship exists between development and aging (Zwaan 2003;Gavrilov & Gavrilova 2004;Mentis & Kararizou 2010). The developmental programming concept (Gluckman et al. 2010) is actually part of a larger conceptual framework of developmental plasticity, where one genotype can give rise to different phenotypes in response to different environmental conditions during development (Bateson 2001;Bateson et al. 2004). ...
... Thus, telomere attrition may serve as an integrative marker of the negative impact of an individual's early life adverse experience, and hence of that individual's future prospects (Epel 2009;Blackburn & Epel 2012;Price et al. 2013;Shalev et al. 2013aShalev et al. , b, 2014Monaghan 2014;Bateson 2016). Since telomeres shorten most rapidly during early life (Heidinger et al. 2012), there is scope for exposures during this period to have a particularly large impact (Gavrilov & Gavrilova 2004). ...
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Later-life health is patterned by socioeconomic influences across the lifecourse. However, the pathways underlying the biological embedding of socioeconomic status (SES) and its consequences on downstream morbidity and mortality are not fully understood. Epigenetic markers like DNA methylation (DNAm) may be promising surrogates of underlying biological processes that can enhance our understanding of how SES shapes population health. Studies have shown that SES is associated with epigenetic aging measures, but few have examined relationships between early and later-life SES and DNAm sites across the epigenome. In this study, we trained and tested DNAm-based surrogates, or “biomarkers,” of childhood and adult SES in two large, multi-racial/ethnic samples of older adults—the Health and Retirement Study (HRS) (N=3,527) and the Multi-Ethnic Study of Atherosclerosis (MESA) (N=1,182). Both biomarkers were associated with downstream morbidity and mortality, and these associations persisted after controlling for measured SES, and in some cases, epigenetic aging clocks. Both childhood and adult SES biomarker CpG sites were enriched for genomic features that regulate gene expression (e.g., DNAse hypersensitivity sites and enhancers) and were implicated in prior epigenome-wide studies of inflammation, aging, and chronic disease. Distinct patterns also emerged between childhood CpGs and immune system dysregulation and adult CpGs and metabolic functioning, health behaviors, and cancer. Results suggest DNAm-based surrogate biomarkers of SES may be useful proxies for unmeasured social exposures that can augment our understanding of the biological mechanisms between social disadvantage and downstream health. Significance Statement Information on DNA methylation (DNAm)—an epigenetic modification that plays a central role in regulating gene expression—is increasingly available in large epidemiological studies. Since DNAm is relatively stable but responsive to environmental influences, genome-wide signatures are promising surrogates or biomarkers of exposure that may both shed light on biological mechanisms between adverse environments and downstream health and/or act as proxies for unmeasured exposures. To better understand the biological embedding of social disadvantage, this study trained and tested DNAm-based surrogates of childhood and adult socioeconomic status (SES) in two US-based cohorts of older adults. Findings reveal distinct DNAm signatures of SES that connect social adversity across the lifecourse with dysregulated immune system responses, inflammatory pathways, poorer metabolic functioning, chronic diseases, and cancer.
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... Thus, telomere attrition may serve as an integrative marker of the negative impact of an individual's experience on its state, and hence of that individual's future prospects (Epel 2009;Shalev et al. 2013b;Monaghan 2014;Bateson 2016). Since telomeres shorten most rapidly during early life (Heidinger et al. 2012), it has been proposed that early-life damage may have a particularly large impact on aging and longevity (Gavrilov & Gavrilova 2004). Exposure to diverse stressors as well as elevated glucocorticoid (stress hormone) concentrations have been demonstrated to accelerate telomere attrition, in ovo, in utero, during post-natal development and in adulthood (Monaghan 2014;Haussmann & Heidinger 2015). ...
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Phenotypic and transcriptomic evidence of early cardiac aging, and associated mechanisms, were investigated in young to middle-aged male mice (C57Bl/6; ages 8, 16, 32, 48 wks). Left ventricular gene expression (profiled via Illumina MouseWG-6 BeadChips), contractile and coronary function, and stress-resistance were assessed in Langendorff perfused hearts under normoxic conditions and following ischemic insult (20 min global ischemia-45 min reperfusion; I-R). Baseline or normoxic contractile function was unaltered by age, while cardiac and coronary ‘reserves’ (during β-adrenoceptor stimulation; 1 μM isoproterenol) declined by 48 wks. Resistance to I-R injury fell from 16 to 32 wks. Age-dependent transcriptional changes In un-stressed hearts were limited to 104 genes (>1.3-fold; 0.05 FDR), supporting: up-regulated innate defenses (glutathione and xenobiotic metabolism, chemotaxis, interleukins) and catecholamine secretion; and down-regulated extracellular matrix (ECM), growth factor and survival (PI3K/Akt) signaling. In stressed (post-ischemic) myocardium, ~15-times as many genes (1528) were age-dependent, grouped into 6 clusters (>1.3-fold change; 0.05 FDR): most changing from 16 wks (45 % up/44 % down), a further 5 % declining from 32 wks. Major age-dependent Biological Processes in I-R hearts reveal: declining ATP metabolism, oxidative phosphorylation, cardiac contraction and morphogenesis, phospholipid metabolism and calcineurin signaling; increasing proteolysis and negative control of MAPK; and mixed changes in nuclear transport and angiogenic genes. Pathway analysis supports reductions in: autophagy, stress response, ER protein processing, mRNA surveillance and ribosome/translation genes; with later falls in mitochondrial biogenesis, oxidative phosphorylation and proteasome genes in I-R hearts. Summarizing, early cardiac aging is evident from 16 to 32 wks in male mice, characterized by: declining cardiovascular reserve and stress-resistance, transcriptomic evidence of constitutive stress and altered catecholamine and survival/growth signaling in healthy hearts; and declining stress response, quality control, mitochondrial energy metabolism and cardiac modeling processes in stressed hearts. These very early changes, potentially key substrate for advanced aging, may inform approaches to healthy aging and cardioprotection in the adult heart.
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The emergence of the developmental origins of health and disease hypothesis, also known as fetal programming or the Barker hypothesis, was derived from the observed long-term effects on adult health from a low birth weight. The first studies pointing at relationships between early life experience and adult health were presented by Forsdahl and Wadsworth. However, it was with Barker’s works that the scientific community gained awareness about the contribution of the gestational environment to the long-term health of the offspring. These and other more recent studies revealed a strong relationship between fetal growth restriction and adult sequelae, demonstrating that adults who were small at birth, but not premature, were at an increased risk for coronary heart disease. Association of hypertension to health status at birth was also corroborated by an epidemiological study using a Finish cohort of approximately 6000 subjects. During the Dutch famine, from 1944 to 1945, investigators could determine the impact of undernutrition in early, mid or late gestation on birth weight. Babies exposed to famine only during early gestation still presented a normal birth weight, but an augmented incidence of coronary heart and renal diseases in later life compared with non-exposed individuals. Another interesting finding was the existence of a conditional adaptive response by the fetus, which confers a survival advantage when the postnatal diet remains suboptimal, but becomes harmful when postnatal nutrition is adequate or in excess. In agreement with epidemiological human observations, studies in rodents, sheep, and non-human primates report accelerated F1 aging and early disease development induced by maternal nutrition during pregnancy.
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  • Jun 2024
  • P NATL ACAD SCI USA
To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.
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Exploring Patterns of Human Mortality and Aging: A Reliability Theory Viewpoint
Article
  • Mar 2024
The most important manifestation of aging is an increased risk of death with advancing age, a mortality pattern characterized by empirical regularities known as mortality laws. We highlight three significant ones: the Gompertz law, compensation effect of mortality (CEM), and late-life mortality deceleration and describe new developments in this area. It is predicted that CEM should result in declining relative variability of mortality at older ages. The quiescent phase hypothesis of negligible actuarial aging at younger adult ages is tested and refuted by analyzing mortality of the most recent birth cohorts. To comprehend the aging mechanisms, it is crucial to explain the observed empirical mortality patterns. As an illustrative example of data-directed modeling and the insights it provides, we briefly describe two different reliability models applied to human mortality patterns. The explanation of aging using a reliability theory approach aligns with evolutionary theories of aging, including idea of chronic phenoptosis. This alignment stems from their focus on elucidating the process of organismal deterioration itself, rather than addressing the reasons why organisms are not designed for perpetual existence. This article is a part of a special issue of the journal that commemorates the legacy of the eminent Russian scientist Vladimir Petrovich Skulachev (1935-2023) and his bold ideas about evolution of biological aging and phenoptosis.
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Early-Life Adversity Associations With Later Life Epigenetic Aging Profiles in the Multi-Ethnic Study of Atherosclerosis
Article
  • Aug 2023
Epigenetic biomarkers of accelerated aging have been widely used to predict disease risk and may enhance our understanding of biological mechanisms between early life adversity and disparities in aging. With respect to childhood adversity, most studies have used parental education or childhood disadvantage and/or have not examined the long reach of socio-emotional or physical abuse and trauma on epigenetic profiles at older ages. This study leveraged data from the Multi-Ethnic Study of Atherosclerosis (MESA) on experiences of threat and deprivation in participants' early lives (i.e., before the age of 18) to examine whether exposure to specific dimensions of early life adversity are associated with epigenetic profiles at older ages that are indicative of accelerated biological aging. The sample included 842 respondents in MESA with DNA methylation data collected between 2010-2012 who answered questions on early life adversities in a 2018-2019 phone follow-up. We find experiences of deprivation, but not threat, are associated with later-life GrimAge epigenetic aging signatures that were developed to predict mortality risk. Results indicate smoking behavior partially mediates this association, which suggests lifestyle behaviors may act as downstream mechanisms between parental deprivation in early life and accelerated epigenetic aging in later life.
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Season of Birth and Human Longevity
Article
Full-text available
  • Dec 1999
  • J Anti Aging Med
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When Does Human Longevity Start?: Demarcation of the Boundaries for Human Longevity
Article
Full-text available
  • Jun 2001
  • J Anti Aging Med
The scientific debates on the future of human life span and its possible biological limits re- vealed a great need for direct identification of longevity boundaries, if they really exist. The key question posed in this study is as follows: how can we possibly determine the age when human longevity starts? To address this problem, we studied the familial transmission of hu- man life span from parents to daughters, since daughters did not have a high incidence of vi- olent causes of death due to military service and are particularly responsive to parental life span. We found that the familial transmission of human life span from mother to daughter is essentially nonlinear with virtually no daughter-mother life span resemblance for shorter- lived mothers (died before age 85) and very high familial resemblance (additive heritability) for longer-lived mothers. This indicates that maternal age of 85 years could be considered as a demarcation point (lower boundary) for female longevity. Women who live above this age are fundamentally (presumably genetically) different from other women in the sense that their daughters live significantly longer. Thus, the age of 85 years could be considered as a threshold age when women mortality becomes much more selective. A similar study of fa- milial transmission of human life span from father to daughter revealed a demarcation point at 75 years, suggesting that this age might represent a lower boundary for male longevity. These results are also consistent with predictions of the evolutionary theory of aging and mu- tation accumulation theory in particular, namely that the additive genetic variance for human life span should increase with parental longevity. In other words, human mortality should become more selective at advanced ages, and this prediction is confirmed in the present study.
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On the Nature of the Function Expressive of the Law of Human Mortality and On a new Mode of Determining Life Contingencies
Article
  • Jan 1825
Dear Sir, The frequent opportunities I have had of receiving pleasure from your writings and conversation, have induced me to prefer offering to the Royal Society through your medium, this Paper on Life Contingencies, which forms part of a continuation of my original paper on the same subject, published among the valuable papers of the Society, as by passing through your hands it may receive the advantage of your judgment.
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A Statistical Distribution Function of Wide Applicability
Article
  • Sep 1951
This paper discusses the applicability of statistics to a wide field of problems. Examples of simple and complex distributions are given.
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Free radical theory of aging: Beneficial effect of adding antioxidants to the maternal mouse diet on life span of offspring; possible explanation of the sex difference in longevity
Article
  • Oct 1979
Endogenous free radical reactions may have an adverse effect on the life span. Based on this possibility a number of free radical reaction inhibitors have been shown to increase the average life span of mice when added to the diet throughout life starting shortly after weaning. The purpose of this study was to determine if exposure to free radical reaction inhibitors, by including them in the maternal diet during the period of about 40 days of high mitotic and metabolic activity between conception and weaning, would also increase the life span. This was found to be the case. The largest increase in average life span was obtained by adding 0.5 percent by weight of the water soluble compound, 2-mercaptoethylamine, to the maternal diet; the increase was 14.7 percent for male offspring and 8.6 percent for females. Consideration of the data of this study in the light of early events in embryogenesis, led to the suggestion that the greater longevity of females is due, at least in part, to greater protection of female embryos from free radical reaction damage during the period before random inactivation of one of their two X-chromosomes.
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