Reviewing the Development of Senotherapeutics to Treat Aging

Senescent cells accumulate with age and contribute meaningfully to chronic inflammation and degenerative aging. Destroying these cells produces rapid and sizable reversal of age-related diseases in mice, demonstrating that the presence of senescence cells acts to maintain a more dysfunctional, inflamed metabolism. This is well known by now, and numerous biotech companies in the first wave of development of senolytic treatments to selectively destroy senescent cells are in varying stages of preclinical and clinical development. Meanwhile, the off-label use of dasatinib and quercetin, a low-cost senolytic therapy that is neither developed nor promoted by any company, continues to look promising based on the slow progression of clinical trials.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflammageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals.

Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity.


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