Cellular senescence is a fundamental mechanism of aging characterised by a stable arrest of the cell cycle in response to stressors such as DNA damage, telomere shortening, and oncogenic signalling. While this process initially serves beneficial roles in tumour suppression, wound healing, and embryonic development, the accumulation of senescent cells over time drives tissue dysfunction and chronic diseases. A primary driver of this pathology is the senescence-associated secretory phenotype (SASP), a complex mix of pro-inflammatory cytokines, chemokines, and proteases secreted by senescent cells that triggers chronic sterile inflammation—often termed 'inflammaging'—and damages neighbouring tissues. The 'Geroscience Hypothesis' posits that targeting these fundamental aging mechanisms can delay the onset of multiple age-related comorbidities simultaneously, rather than treating them individually.
To address this, researchers have developed senotherapeutics, which are broadly categorised into senolytics and senomorphics. Senolytics are drugs designed to selectively kill senescent cells by targeting senescent cell anti-apoptotic pathways (SCAPs), such as the BCL-2 family or PI3K/AKT networks, which allow these cells to resist apoptosis despite their damaged state. The first reported senolytic regimen, a combination of dasatinib and quercetin (D+Q), has been shown to reduce senescent cell burden in human adipose tissue and improve physical function in patients with idiopathic pulmonary fibrosis. Other agents, such as navitoclax, target BCL-2 proteins but are associated with dose-limiting toxicities like thrombocytopenia. Natural flavonoids such as fisetin are also being investigated for their potential to extend healthspan and reduce inflammation.
In contrast, senomorphics do not eliminate senescent cells but instead suppress their detrimental phenotypes, particularly the SASP, by modulating pathways such as NF-κB, p38MAPK, and mTOR. Rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR), is considered the most robust pharmacological intervention for extending mammalian lifespan. By inhibiting mTOR complex 1 (mTORC1), rapamycin mimics the effects of caloric restriction, reactivates autophagy, and dampens the SASP, effectively shifting cellular function from anabolic growth to repair and maintenance. Recent preclinical studies indicate that combining rapamycin with other geroprotectors, such as trametinib, may provide additive benefits for longevity.
Emerging frontiers in this field include immunotherapeutic approaches, such as senolytic vaccines and chimeric antigen receptor (CAR) T cells engineered to target surface antigens like uPAR or GPNMB, offering high specificity in clearing senescent cells. However, clinical translation faces hurdles due to the high heterogeneity of senescent cells across different tissues and the risk of interfering with the beneficial physiological roles of senescence in tissue repair. Successful implementation of these therapies could result in a 'longevity dividend', creating substantial economic value by compressing morbidity and extending the healthy, productive years of life.
