Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

Abstract

Aging is a physiological decline in both structural homeostasis and functional integrity, progressively affecting organismal health. A major hallmark of aging is the accumulation of senescent cells, which have entered a state of irreversible cell cycle arrest after experiencing inherent or environmental stresses. Although cellular senescence is essential in several physiological events, it plays a detrimental role in a large array of age-related pathologies. Recent biomedical advances in specifically targeting senescent cells to improve healthy aging, or alternatively, postpone natural aging and age-related diseases, a strategy termed senotherapy, have attracted substantial interest in both scientific and medical communities. Challenges for aging research are highlighted and potential avenues that can be leveraged for therapeutic interventions to control aging and age-related disorders in the current era of precision medicine.

Keywords: aging; clinical trials; healthspan; senescent cells; senolytics; senotherapy.

Figure 1

The canonical hallmarks of aging, its accompanying chronic diseases and potential interventions. Aging is characterized by a set of typical hallmarks, including genomic instability, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, telomere attrition, deregulated nutrient sensing, stem cell exhaustion, and cellular senescence. During natural aging, the incidence of age‐related pathologies increases in a progressive manner, most of which implicate cellular senescence. Therapeutic avenues involving genetic, dietary, or pharmacologic approaches have emerged as potent intervention strategies to prevent or ameliorate aging symptoms, although with different mechanisms. Given that the aged population in a global range is drastically increasing and that aging outstands as the greatest risk factor for the vast majority of chronic diseases responsible for both morbidity and mortality, it is critical, urgent and sagacious to expand geroscience aimed at improving human healthspan. Note, the course of organismal aging is indeed accompanied by various natural activities such as revolution of planets in the universal setting, day and night (exemplified as symbols at the corners of the circle). Part of the figure (mainly the circle) is adapted with permission.^{[ 164 ]} Copyright year 2020, CellPress.

Figure 2

Emerging strategies that showed efficacy in targeting cellular senescence. At late or advanced stages of life, senescent cells progressively accumulate in multiple tissue types and substantially promote the development of multiple age‐related diseases. Increasing lines of studies suggest that targeting specific fundamental mechanisms of aging may be more effective than treating each chronic pathology individually to restrain the impacts of aging on healthspan and lifespan. Pilot trials have been initiated to therapeutically target cellular senescence, such as A) selectively removing senescent cells via induction of their death (senolytic treatment), and B) engagement of the immune surveillance (senescence‐directed immunotherapy), with the potential of each strategy in depleting senescent cells from tissue microenvironment demonstrated by recent investigations. In each mechanistic illustration, yellow arrows mean stimulating or promotive actions, while red arrows represent suppressive or counteractive functions. A) Agents within yellow rectangles are example senolytics. B) Scissors represent shedding of NKG2D ligands by MMPs secreted by senescent cells, especially those induced by oncogene activation. (A) adapted with permission.^{[ 164 ]} Copyright year 2020, CellPress. We stated “Figure (A) adapted with permission [164]. Copyright year 2020, CellPress.” Please refer to Page 33 (Figure legend, Figure 2).

Figure 3

A hypothetic model to illustrate senotherapy‐mediated healthy aging. The first stage of the survival curve refers to the pre‐mortality plateau phase (PPP), during which ≈10% of the overall population is lost over a relatively long period. Alternatively referred to as a healthy lifespan, the PPP covers three sub‐stages, including an adolescent period when the body actively develops, a young adult period when the individual is physiologically mature, and a middle‐aged period when the mortality rate begins to increase. During the overall PPP span, 90% of the population remains alive, after which the mortality rate significantly arises and the population declines rapidly, a period constituting the late‐aged phase. However, in the case of senotherapy which theoretically comprises multiple waves of medications with senolytics administered in an intermittent or metronomic manner, the lifespan can be remarkably extended. Senotherapy can eliminate senescent cells, promote tissue repair, improve organ regeneration, and ameliorate multiple age‐related pathologies, thus providing a prominent avenue for a healthier aging of human populations.^{[ 165} , ^{166 ]}