Senolytic drugs that destroy senescent cells, and later on, other senotherapies that either prevent senescence or block the senescence-associated secretory phenotype (SASP), are going to be very important in the treatment of aging. Senescent cells accumulate with age and are highly damaging to tissues. Via the SASP, even comparatively small numbers of lingering senescent cells actively disrupt health and tissue function, driving age-related disease and mortality. Removing these errant cells causes quite rapid rejuvenation in animal studies, meaningfully reversing the progression of numerous age-related conditions. Other approaches to the treatment of aging attempted to date have so far failed to produce results that are as robust and impressive as the data emerging from the study of senolytics. Within a few years we’ll know just how well that translates to humans for at least a few conditions, as a number of clinical trials are presently underway or planned.

Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine.

Multiple interventions that target primary aging processes are currently being explored. Senescent cell burden represents one fundamental aging process that has been carefully studied. Targeting it at the preclinical level by genetic and pharmacologic reduction has yielded compelling findings that support the geroscience hypothesis. Translation of promising pharmacologic interventions in the form of senotherapeutic agents has begun to assess safety and target engagement.

Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine. Clinically relevant primary endpoints for older adults will likely include aspects of both objective and subjective physical functioning, since these are predictive of morbidity and mortality, contribute to risks of cognitive decline and injury, are prominent components of geriatric syndromes, and are consistent with measurable improvements being made in the short term. Biomarkerdiscovery will be facilitated by larger clinical trials, measurement of changes in multiple analytes in multiple target specimens, and replication of biomarker feasibility and utility across multiple sites within a single study and among different studies. In the longer term, it should be possible to assess the delays in onset of chronic diseases and geriatric syndromes with compression of morbidity, using interventions based on reduction of senescent cell burden and other interventions in the aging process.

Link: https://doi.org/10.1016/j.molmed.2020.03.005

Source: Fight Aging!