Invited Commentary: Epigenetic Clocks and Obesity—Towards the Next Frontier Using Integrative Approaches and Early-Life Models

Abstract

Why people of the same age show differences in age-related functional decline and whether biological aging can be slowed down through lifestyle changes and therapeutics are active research topics. Molecular tools that predict biological age based on DNA methylation markers, known as epigenetic clocks, are facilitating these efforts. In this issue, Kresovich et al. (Am J Epidemiol. 2021;190(6):984–993) investigated a cohort of non-Hispanic White women, demonstrating positive relationships between adiposity measures and the ticking rate of epigenetic clocks in blood. This commentary emphasizes that integrating molecular and genetic epidemiology approaches is crucial to dissecting the complex relationship between obesity and epigenetic aging. The early-life period is explored as a unique opportunity to gain novel insights into links between developmental processes and aging in later life. Last, the landscape of the next frontier in aging research is described in light of the imperative for transdisciplinary approaches to outline a shared vision and public health implementation dilemmas.

Editor’s note: The opinions expressed in this article are those of the author and do not necessarily reflect the views of the American Journal of Epidemiology.

Aging has always been a topic of human inquiry because of its ties with quality of life, disease, and mortality. An everyday observation that equally intrigues the public as well as scientists is why people of the same age manifest differences in age-related physical and cognitive declines. Myriad aging theories have been put forward by scientists to figure out the concept of aging, its causes, and related consequences. Perhaps a comprehensive definition of aging at the molecular and cellular level is the presence of 9 hallmarks (1). Among those hallmarks, epigenetic alteration has emerged as a widely used molecular tool for measuring biological aging, a complex phenomenon associated with a decline in cellular and organ functions.

DNA methylation is one of the epigenetic mechanisms that regulate the packaging of genetic information and gene expression. As we age, the amount of methylation (i.e., the addition of a methyl “cap” that represses expression of some genes) is altered. This observation led to the first-generation DNA methylation age predictor based on methylation levels of a set of methylation sites (2). The discrepancy between DNA methylation age and chronological age, known as epigenetic age acceleration, indicates whether the biological age of a tissue is older or younger than its chronological age. These DNA methylation age predictors, commonly known as epigenetic clocks, have remarkable features of a biological age estimator, such as highly accurate correlation with a person’s chronological age, trans-tissue portability, and ability to predict health and lifespan more accurately than chronological age (2). Consequently, epigenetic clocks attract active research to understand environmental exposures, lifestyle factors, and molecular processes that can be targeted to promote healthy aging and extend human lifespan.

OBESITY AND EPIGENETIC AGE ACCELERATION—EVIDENCE FOR PAN-TISSUE RELATIONSHIPS?

Kresovich et al. (3) investigated whether adiposity measures (i.e., body mass index, waist-to-hip ratio, and waist circumference) and recreational physical activity are associated with 6 measures of epigenetic age acceleration in blood. Using data from 2,758 non-Hispanic White women (mean age, 57 years), the study found consistent positive association between adiposity and epigenetic age acceleration. Obesity continues to be a rising public health crisis and is linked with increased risk of aging-related chronic diseases and mortality. Therefore, insights into the relationships between obesity and biological aging have tremendous significance in pinpointing clinical and public health intervention targets.

Perhaps it is time to reconstruct our understanding regarding the types of tissues in which epigenetic aging is accelerated in relation to obesity. Based on relatively smaller study cohorts, it was thought that there is obesity-related epigenetic age acceleration in liver, adipose, and buccal tissues but not in blood (4–6). Those null or inconsistent associations between obesity and epigenetic clocks in blood had to await the test of well-powered and population-representative studies. Recent studies including the Women’s Health Initiative, which enrolled more than 4,100 postmenopausal women, found positive associations between obesity measures and some epigenetic clocks in blood (7–10). In addition to reinforcing findings of those latter studies, a key strength of Kresovich et al. (3) is the multiple body composition measures tested against different types of epigenetic age acceleration metrics. The concurrence of the recent study findings in support of obesity-related epigenetic age acceleration in blood is a clear shift of evidence that raises additional biomedical research questions.

From a clinical standpoint, blood samples are more accessible than metabolically active tissues such as liver, adipose, or muscle tissues, and hence have better potential for clinical and public health utility. However, it is important to recognize that methylation regulation in aging is tissue-specific (11). Further investigation is required to understand whether the obesity-related epigenetic aging in blood recapitulates the biological aging process in metabolically active tissues, is an independent phenomenon related to metabolic and immunologic changes in blood, or is a mix of both.

DISENTANGLING THE DIRECTION OF THE RELATIONSHIP BETWEEN OBESITY AND EPIGENETIC AGING

It is currently unknown whether obesity is a driver or consequence of epigenetic age acceleration. There is a need to confront this challenging question not just out of scientific curiosity but to address consequential public health dilemmas: Do we want to focus on interventions that help slow down biological aging or those that target weight control? A vicious and complex relationship between aging and obesity is plausible given the cellular and molecular phenotypic signatures they share. Aging-related cellular senescence contributes to metabolic impairments manifesting as obesity, type 2 diabetes, and insulin resistance through accrual of visceral fat and proinflammatory cytokines (12). In turn, obesity can drive aging through inhibition of cellular maintenance mechanisms (13). As we age, the distribution of adipose tissue shifts from subcutaneous to visceral fat, precipitating obesity risk as well as the aging process (14). These physiological changes in body composition during the life course could partly explain age-dependent relationships observed between adiposity and biological aging (9). Longitudinal studies that examine changes in obesity measures and epigenetic age acceleration over time can lend some insights, and have been attempted in a couple of small cohort studies but remain inconclusive (7, 9).

When dealing with complex phenotypes such as biological aging and obesity, it is important to recognize the central role of inherited genetics. Genetic sequence variation explains a substantial portion of DNA methylation differences (15). Genetic factors regulate the ticking rate of the epigenetic clock (16, 17) as well as obesity (18). Environmental exposures and lifestyle factors that predispose to obesity risk are also associated with faster biological aging. Some genetic factors influence both epigenetic aging and obesity, adding complexity to research that attempts to dissect the causal direction in obesity–biological aging relationship (17).

For genetic epidemiologists, analysis approaches such as Mendelian randomization provide a powerful alternative to randomized controlled trials to investigate causality between phenotypes. An advantage of Mendelian randomization over traditional observational studies is that it is not distorted by confounders because it leverages the random genotype assignment during meiosis. Recently developed Mendelian randomization approaches implement summary statistics of genome-wide association studies to construct genetic instrumental variables and predict exposure-outcome causal relationship (19). While a valid instrumental variable can be constructed for obesity phenotypes based on known obesity-related genetic variants from existing genetic studies (18), the genetic architecture of epigenetic age acceleration is not clearly known. Future large cohort studies into the genetic basis of epigenetic age acceleration can be valuable to clarify the biological underpinnings of epigenetic age acceleration and to construct causal relationships between epigenetic clocks and aging-related phenotypes such as obesity. Here it is worth acknowledging that the biology of aging and obesity is complex, whereas Mendelian randomization and other molecular tools are only as good as their assumptions. Therefore, we have an imperative to be cautious during interpretation, and the findings should be validated, for example, using other techniques and independent data sets. We should also ask ourselves or others in other disciplines whether the findings make biological sense.

NOVEL INSIGHTS ABOUT BIOLOGICAL AGING CAN BE GAINED FROM EARLY-LIFE TISSUES

To precisely guide interventions aimed at manipulating biological aging and age-related conditions such as obesity, it is critical to integrate epidemiologic studies with molecular and genomics approaches. There is still a lack of clarity in understanding what epigenetic clocks measure and their biological underpinnings. Perhaps the time is right to recommend considerable commitment to aging research at early life stages. Two outstanding benefits are worth mentioning: to understand the biology of aging and to gain novel insights about links between developmental processes and aging in later life. First, the early-life period offers entirely new opportunities to study the mechanisms of aging from the perspective of growth and development. Growth-inhibiting conditions such as calorie restriction and rapamycin also decelerate aging; hence, recognition of aging as a continuation of developmental growth rather than an opposite phenomenon is gaining traction. This is appealing given cumulative evidence in support of quasiprogramming of aging, in which aging and growth are considered to be mechanistically similar (20).

Second, early-life studies are valuable to understand developmental conditions that can contribute to the biological aging trajectory of a tissue or an individual. Epigenetic age acceleration at birth and childhood have been associated with prospective developmental characteristics (21). Maternal smoking and alcohol consumption during the prenatal period have been associated with accelerated epigenetic aging in children (22). The ticking rate of the epigenetic clock appears to be accelerated before adulthood and remains remarkably stable thereafter (2, 23). How epigenetic age acceleration is related to growth and development in early life remains unexplored, but it could hold the keys to important biological insights about aging throughout life.

Short-lived in-utero organs and tissues can be useful life-course models to gain novel insights about biological aging in early life. For example, the placenta is a transient organ during pregnancy that undergoes physiological growth, aging, calcification, and death over a period of just ~40 weeks in humans. A recent study demonstrated that placental epigenetic age acceleration influences the growth of male fetuses more strongly than female fetuses, suggesting that the biological aging rate of placenta can partly explain the well-known male fetus vulnerability to adverse obstetrical outcomes (24). Placental epigenetic age acceleration is under substantial genetic control (25). Genetic studies can give novel clues about the molecular basis of the ticking rate in early life, with implications for understanding aging in later life.

THE NEXT FRONTIER: IS SLOWING BIOLOGICAL AGING WITHIN REACH?

The extent to which epigenetic age acceleration is modifiable is still unclear. Research on the relationships of biological aging with lifestyle factors related to positive health outcomes might provide clues. Conventional lifestyle and dietary recommendations in public health can contribute to slower biological aging (7). Kresovich et al. (3), consistent with the largely null findings of published studies (7, 26, 27), did not find association between recreational physical activity and epigenetic age acceleration for 5 of 6 epigenetic age acceleration metrics tested. However, results suggested that recreational physical activity might attenuate the link between obesity and acceleration of the epigenetic clock. This is good news.

The timely question in biological aging studies is whether and how epigenetic age acceleration can be slowed down or reversed. In studies, weight-loss treatment and exercise interventions did not reverse or slow epigenetic age acceleration, despite noticeable changes in metabolic and DNA methylation profiles in liver and adipose tissues (4, 28). Unexpectedly, a clinical study found reversal of the epigenetic age of 9 healthy volunteers who were on a 1-year regimen of growth hormone and diabetes medications (29). Although the findings await validation by rigorously controlled studies, the remarkable reversal of the biological clock by up to 2.5 years within a year of intervention is provocative. Future studies can inform the extent to which the rate of biological aging can be slowed down by modifiable lifestyle factors and novel therapeutics.

For the scientific community, these studies also signal the need for transdisciplinary approaches to outline a shared goal in aging studies. It falls upon the entirety of researchers to recognize that epigenetic clocks are promising molecular tools, but their clinical utility is yet undemonstrated. If successful, these revolutionary techniques could challenge long-held assumptions about aging. Therefore, the early phases of research offer opportunities to begin discussion on communication strategies about biological aging, ethical issues, and equitable access to biomedical interventions that might improve healthy aging and quality of life.