Biological aging is a complex, multifaceted process characterized by the gradual decline of physiological and cognitive functions over time. While certain hallmarks of biological aging, such as cellular damage, genomic instability, and loss of homeostatic regulation, have been identified, the mechanisms that drive these changes remain poorly understood. Compensatory and resilience mechanisms, which help maintain stability and function in the face of stress or damage, are active throughout life but decline with age, contributing to the unrepaired damage and onset of frailty and disease. The interplay between resilience mechanisms and accumulated damage underlies variability in aging trajectories and highlights the need to evaluate both repair and damage processes.1 Although studies in animal models and human subjects have started to elucidate these processes, much of the biology of aging remains elusive. Fully understanding these mechanisms is essential for unraveling the nuances of biological aging and developing interventions with clinically significant health impacts.
Cellular senescence is a stress response in which cells permanently stop dividing and undergo changes in morphology, chromatin structure, secretory profile, and protein expression. Often, it is triggered by DNA damage, telomere shortening, oxidative stress, oncogene activation, and other stressors.2 Senescent cells secrete pro-inflammatory factors, resist apoptosis, and accumulate in tissues, often contributing to age-related degeneration and diseases such as osteoarthritis, pulmonary fibrosis, diabetes, atherosclerosis, and Alzheimer’s.3 Quantifying senescence in humans is challenging due to the variety of heterogeneous triggers and a lack of truly specific biomarkers, but emerging approaches show promise for how researchers can use cellular senescence to assess biological aging.
Epigenetic clocks track age-related changes in DNA methylation, which is one of the most robust and clinically promising biomarkers of biological aging. Epigenetic changes in early-life and developmental stages may be initially adaptive but can become maladaptive, contributing to chronic diseases. For example, the innate search for food can benefit a newborn but contribute to diabetes in the adult.4 Continuous epigenetic tuning throughout an individual’s lifespan reflects the cumulative response to both environmental and internal stress. Measuring these methylation patterns, including “epigenetic acceleration,” provides a window into an individual’s biological age and may guide interventions that aim to slow aging and improve health outcomes.1
The repair, recycling, and elimination of damaged macromolecules/organelles, through processes such as autophagy, protein biogenesis, proteasomal degradation, and more, are critical for maintaining cellular function. However, these processes become less efficient with aging.5 Compounds such as rapamycin, spermidine, resveratrol, and urolithin A can enhance autophagy and improve cellular and mitochondrial health, which seems to protect against certain age-related diseases. In a 2011 study, the polyphenol resveratrol was shown to increase longevity in mice.6 Developing reliable assays to measure autophagy in humans is a formidable task, but such measures could serve as valuable biomarkers of biological aging and guide future interventions to preserve cellular resilience and improve human health.
Developing a robust, precise, and reliable estimator of biological aging is a critical investment for advancing research in biological aging and addressing multimorbidity and disability in aging populations. Ideally, such measures would be minimally invasive, affordable, and able to track biological aging independently of chronological age, allowing identification of individuals at higher risk for disease or functional decline. Understanding biological aging would enable clinicians to target interventions while resilience and compensatory mechanisms are still intact, rather than waiting until multiple diseases have already developed.1 Longitudinal tracking of biological aging could reveal genetic, environmental, and behavioral factors that each influence accelerated aging, guide personalized therapies, and inform clinical trial design. Validated biomarkers of biological aging have the potential to transform geriatric and preventive medicine, as well as therapeutic development by shifting the focus from treating existing disease to maintaining resilience and slowing the aging process.
References
- Ferrucci L., Gonzalez‐Freire M., Fabbri E., et al. Measuring Biological Aging in Humans: A Quest. Aging Cell. 2019;19(2). https://doi.org/10.1111/acel.13080
- Childs B.G., Durik M., Baker D.J., van Deursen J.M., Cellular Senescence in Aging and Age-Related Disease: From Mechanisms to Therapy. Nature Medicine. 2015;21(12):1424-1435. https://doi.org/10.1038/nm.4000
- Baker D.J., Petersen R.C., Cellular Senescence in Brain Aging and Neurodegenerative Diseases: Evidence and Perspectives. Journal of Clinical Investigation. 2018;128(4):1208-1216. https://doi.org/10.1172/jci95145
- Barker D.J.P., Osmond C., Winter P.D., Margetts B., Simmonds S.J., Weight in Infancy and Death from Ischaemic Heart Disease. The Lancet. 1989;334(8663):577-580. https://doi.org/10.1016/s0140-6736(89)90710-1
- Cuervo A.M., Bergamini E., Brunk U.T., Dröge W., Ffrench M., Terman A., Autophagy and Aging: The Importance of Maintaining “Clean” Cells. Autophagy. 2005;1(3):131-140. https://doi.org/10.4161/auto.1.3.2017
- Agarwal B., Baur J.A., Resveratrol and Life Extension. Annals of the New York Academy of Sciences. 2011;1215(1):138-143. https://doi.org/10.1111/j.1749-6632.2010.05850.x