Healthy Eating Patterns: A Stealthy Geroscience-Guided Approach to Enhancing the Human Healthspan

The clinical benefits of healthy eating patterns are increasingly clear from both interventional and epidemiological studies. In a recent study, Shan et al. examined associations of four different self-reported healthy eating patterns with the risk of total and cause-specific mortality in two large prospective cohorts with up to 36 years of follow-up¹. In discussing the strengths and limitations of this important study, authors acknowledged that residual and unmeasured confounders cannot be absolutely ruled out given the observational nature of this study. Nonetheless, the data convincingly demonstrated that self-reported adherence exposure to any one of four different healthy diet regimens – Healthy Eating Index 2015 (HEI-2015), Alternate Mediterranean Diet (AMED), Healthy Plant-based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI) – was associated with lower rates of overall mortality. Moreover, all dietary scores were significantly inversely associated with death from cardiovascular diseases, cancer and respiratory diseases. Two of the dietary regiments, AMED and AHEI were also significantly inversely associated with death from neurodegenerative diseases. These inverse associations remained consistent across different racial and ethnic groups and among males and females.

In a time of rising health care costs and an aging population, these findings could have an immense public health impact if successfully translated into interventions capable of decreasing the onset and progression, as well as mortality from these highly prevalent and disparate chronic diseases. Moreover, since accessibility to healthy food, as well as time and capability to prepare fresh food are key social determinants of health, successful translation could have a transformative effect on the health impact of social and economic disparities. Most study participants were health professionals, likely highly motivated and without these common barriers. One option for translation is a serious, evidence-guided national commitment to overhauling food quality, removing barriers to healthy food accessibility, and retooling social policies to make fresh food preparation practical and easy for every household. An equally important option is to identify relevant active mechanisms in these dietary patterns to inform more focused policy interventions and pharmaceutical development. The mechanistic lens of geroscience may be the key to unlocking those benefits in the broadest and most equitable way.

The authors understandably make no comment on the molecular mechanisms that might underlie and help explain these remarkable findings. Many factors contribute to the often missed opportunities to gain translational insights from large populations studies. For example, identifying a single mechanism shared by such varied dietary interventions while simultaneously impacting multiple chronic conditions is daunting. Yet, while searching for a single mechanism to help explain the entirety of these observations may seem like a fool’s errand, important insights can be gained from the emerging field of geroscience².

The Geroscience Hypothesis states that interventions targeting biological aging have the potential to slow the onset and progression of varied age-related chronic diseases that contribute to disability, dependence, and death in older adults². Such interventions would expand the healthspan by increasing the number of years an individual remains healthy and independent in late life. The Geroscience Hypothesis arose from three key discoveries. First, our understanding of the underlying biological processes or “hallmarks” of aging has greatly matured in recent years. Second, it has also become apparent that aging represents the largest and shared risk factor for varied chronic diseases and conditions (i.e., CVD, cancer, diabetes, neurodegenerative diseases). Third, the discovery of a growing number of compounds and other interventions with the capacity to modify these hallmarks, has raised the prospect of slowing the rate of biological aging².

However, in spite of robust animal and pre-clinical data, the translation of such interventions into clinical care via geroscience-guided clinical trials has been slow. Impediments to such progress have included skepticism among clinicians who have observed past failures in translation of therapies for conditions such as Alzheimer’s disease from mice to humans, lack of a sufficient workforce in applied translational geroscience, cost of large multi-site clinical trials, and time needed to move from an idea to the completion of such trials³.

In the above context, it is noteworthy that the findings presented by Shan et al.¹ may be viewed as offering unprecedented evidence in support of the geroscience hypothesis. Most importantly, despite the heterogeneity of the interventions examined, they all had beneficial effects on both overall mortality and disease-specific mortality from different chronic conditions with different disease-specific pathophysiologies.

In fact, findings presented by Shan et al.¹ can only be reconciled in one of two ways. These diverse chronic conditions share common risk factors in the form of varied facets of biological aging and each of these heterogeneous dietary interventions exerts a geroscience-guided impact by modifying shared risk factors, thus delaying the onset and/or progression of varied chronic diseases. Alternatively, the Western diet is detrimental to human health, with its negative effects becoming amplified by aging, and thus changing it to any healthier alternative modifies shared risk factors, affecting overall- and disease-specific mortality from widely different chronic conditions. Of course, these two explanations are not mutually exclusive since a growing body of evidence has described a role for diet-induced obesity, malnutrition and varied social determinants of health in accelerating the rate of biological aging⁴.

Nutrition and molecular mechanisms of aging are deeply intertwined. Indeed, dietary interventions have been shown to modify biological pathways and risk factors shared between aging (biological hallmarks of aging) and various chronic diseases. These pathways include nutrient sensing regulation, mitochondrial function, cellular senescence, epigenetic changes, composition of gut microbiota and inflammation. For example, nutrient sensing pathways that can be manipulated through diet, as evidenced by studies of dietary restriction dating to the middle of the 20th century, were among the first mechanisms of aging discovered, resulting in the discovery of many drugs now in early-stage clinical trials to target aging^5,6.

Furthermore, growing evidence indicates that the biological hallmarks of aging do not exist as isolated silos, but are intricately interconnected. The Unitary Theory of Aging posits that influencing a single biological hallmark of aging (e.g. clearing senescent cells with senolytics) will result in favorable functional and clinical effects in part by modifying other biological hallmarks of aging.

In the context of geroscience, mechanisms through which heterogenous dietary patterns impact varied age-related diseases can be readily hypothesized. Particular elements of the default Western pattern of eating may interact negatively with specific aging mechanisms, such as excessive chronic mTOR (mammalian target of rapamycin) activation. Alternatively, the healthy eating patterns in Shan et al. may share a set of positive interactions with downstream aging mechanisms through common elements such as AMPK (AMP-activated protein kinase) activation (small meal size), mTOR inhibition (moderate protein intake), autophagy activation (polyunsatured fats), or microbial epigenetic modifiers (soluble fiber from nuts and legumes)². Either of these hypotheses could generate actionable evidence for food regulations or pharmaceutical development. Importantly, increasing evidence ties such geroscience mechanisms to social determinants of health⁴.

Closer collaboration between the fields of human nutrition and geroscience could elucidate relevant mechanisms for translation. NIH might foster such collaborations through multidisciplinary workshops and specific translational funding opportunities. Geroscience biomarkers should be incorporated into large epidemiological studies of nutrition, as they increasingly are in large aging studies such as the Health and Retirement Study⁷. Uncovering new mechanisms by which to ameliorate the impact of economic and social disparities on diet and ensuing health outcomes should be a key goal.