Niedernhofer, Laura J

Summary A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP ‐1/ CCL 2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 ( MCP ‐1) levels increased in an age‐dependent manner in wild‐type ( WT ) mice. That age‐dependent increase was accelerated in Ercc1 −/Δ and Bubr1 H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1 −/Δ and WT mice lowered serum MCP ‐1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP ‐1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP ‐1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.

Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age‐related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation‐induced damage. Senolytic agents are being tested in proof‐of‐concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long‐term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging‐like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age‐related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time.