One way of looking at human longevity is that it results from a greater resilience to the damage and dysfunction of aging, whether that resilience emerges from lifestyle choice or genetic differences. The research community spends a great deal of effort in attempting to understand how centenarians survive to old age, which of the many differences that can be catalogued are relevant in the sense of producing greater resilience. There is some question as to whether this is a useful way forward for the field; after all, centenarians are frail and exhibit a high mortality rate. It is not a state to aim at. It may be the case that studies will help to determine which of the mechanisms of aging are more versus less important, but the goal of aging research should not be to produce therapies that let people aging slightly more slowly, it should be to produce outright rejuvenation.
Aging represents an intrinsic biological process of all organisms that are affected by time-dependent changes from birth throughout the lifespan. Although the rate and phenotypic expression of aging are known to considerably vary among individuals and species, the process itself is biologically conserved. However, the dynamic of aging is not linearly related to the natural proceeding of time, but it is characterized by a complex and multifactorial nature, a process that is described as biological age. Biological age is indeed a multidimensional measure of the functional and physiological state of an individual that reflects the cumulative effects of genetic background, environmental, and lifestyle factors on the aging process. Unlike chronological age, which is defined by the passage of time since birth, biological age aims to capture the rate of aging and is considered a more accurate indicator of health status, functional capacity, and the risk of age-related diseases and mortality.
From a biomedical perspective, a wealth of determinants, mechanisms, and processes, including genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, and chronic low-grade inflammation, significantly contribute to the aging-related decline in function and homeostasis. The persistent nature of these stressors leads to the accumulation of molecular damage and functional decline across multiple cellular systems. Consequently, aging represents a long-term imbalance between damage generation and resistance/repair mechanisms, ultimately driving the progressive deterioration of cellular and tissue function.
In this review, we conceptually organize the broad range of processes underlying aging into hierarchical levels of complexity, highlighting the convergence of multiple damage, antagonistic, and adaptive mechanisms in the multifaceted loss of resilience. In this context, centenarians can be considered a paradigm of exceptional biological adaptation. Accordingly, we explore this field from a physiological point of view by reviewing the genetic, epigenetic, molecular, and systems-level traits of centenarian populations and animal models, highlighting potential drivers of a favorable balance between damage and repair mechanisms associated with their remarkable longevity.
Link: https://doi.org/10.1016/j.mad.2026.112236
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