Telomeres and Cellular Senescence in Aging

Despite being targets of various immune cells, SCs progressively accumulate in mammalian tissues with advancing age. Ablation of SCs by genetic or pharmacological “senolytic” means in various mouse models of aging and disease results in significant improvement of health and/or lifespan, providing compelling evidence that cellular senescence promotes aging and the development of age-associated disorders. We previously demonstrated that SCs with short and dysfunctional telomeres can be increasingly detected in aging baboons and humans, supporting the model that telomere shortening and dysfunction contribute to SCs accumulation and aging in primates (Herbig et al. 2006 Science; Jeyapalan et al. 2007 Mech Ageing Dev; Fumagalli et al. 2012 Nat Cell Biol; Suram et al. 2012 Embo J) . More recently, we have begun to characterize the reasons for age-associated SC accumulation in mammals. We discovered that some subsets of circulating immune cells also increasingly develop classic features of cellular senescence with advancing donor age, suggesting that the increasing failure of the immune system to clear SCs systemically is due to his age-associated increase in senescent and dysfunctional immune cells (Martinez-Zamudio et al., Aging Cell, 2021). We are now characterizing the functional and biological consequences of various senescent immune cell types with the goal of developing senotherapies that enhance or alter the functions of senescent immune cells during disease and aging, and that suppress their potentially damaging effects in advanced age (Turano et al., under review, 2025; Figure 5).

Potential role for telomere shortening and dysfunction in organismal aging