Human age reversal: Fact or fiction?

Abstract

Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age-related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant-based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non-interventional studies have connected high-quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha-ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.

Keywords: aging clock; biological age; epigenetic age; healthspan; lifespan; longevity; machine learning; mortality.

FIGURE 1

Aging clocks are targetable. (a) With age, the methylome undergoes significant changes characterized by aberrant hypermethylation and hypomethylation. These age‐associated epigenetic changes serve as the basis for epigenetic aging clocks that are thought to measure biological age. (b) Existing evidence suggests that aging clocks are malleable and can be slowed or reversed in response to various interventions, such as caloric restriction, a plant‐based diet, drugs, or lifestyle change involving physical activity