The Redox-Senescence Axis in Aging
The accumulation of senescent cells is an important cause of degenerative aging. These cells secrete a mix of signals that produces chronic inflammation and disrupts tissue maintenance and function. Researchers here note that oxidative stress and oxidative signaling appear to be important in cellular senescence. These aspects of cellular metabolism are influenced by many of the small molecule drugs that have been found to affect senescence, either by slowing the pace at which cells become senescent, or by selectively inducing apoptosis in senescent cells.
Myriad stress stimuli trigger the acquisition of senescence and/or its maintenance, which in addition to promoting tissue repair and remodeling also functions as an effector mechanism driving age-related pathologies. The functional dichotomy of senescence is visibly manifested in regulating signaling networks that suppress or promote the process of carcinogenesis and its progression. These biological responses are a function of the slew of cytokines and chemokines secreted by cells upon acquiring the senescence-associated secretory phenotype (SASP). Despite the current advancement in the understanding of various stimuli and signaling networks upstream and downstream of SASP, there is relative lack of clarity with respect to the temporo-spatial factors/events that govern the switch from the good (onco-suppressor) to the bad (oncogenic).
Importantly, the intricate crosstalk between senescence and cellular redox metabolism has potential therapeutic implications. To that end, it's worth pointing out that a majority of small molecule compounds with senomorphic and/or senolytic activities also elicit redox regulatory effects. The challenge obviously would be to untangle the inherent complexity of the redox-senescence interplay, which will inform the appropriate clinical utility of these strategies as well as selective repurposing of other drugs.
Could regulation of cellular redox status be the common denominator in senolytic and senomorphic strategies? In this regard, aside from the deleterious effects on bio-molecules, aberrant redox signaling, downstream of DNA damage response activation, could be critical in the maintenance of senescence, and as such restoring redox homeostasis could have the dual advantage of blocking the acquisition as well as maintenance of the senescent phenotype. Hence, one might dare to conjecture that, in addition to accumulating oxidant-mediated damage over time, ageing involves a further role for an aberrant redox microenvironment in promoting cellular senescence.