Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

Abstract

Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype (SASP). Senescence is physiologically important for embryonic development, tissue repair and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contribute to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction and organ degeneration. Agents including those targeting damaging components of the SASP or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

“…Meanwhile, the levels of nuclear lamina protein Lamin B1 ( LMNB1 ) and lamina-associated protein LAP2 ( TMPO ) were diminished in EIF4EBP1 −/− hMSCs relative to EIF4EBP1 +/+ hMSCs ( Fig. 1M ), consistent with previous findings in senescent hMSCs ( Bi et al , 2020 ; Diao et al , 2021 ; Sun et al , 2022 ). Furthermore, we observed an accelerated decay of EIF4EBP1 −/− hMSCs in vivo when implanted into the tibialis anterior (TA) muscles of nude mice, suggesting impaired in vivo retention ability of EIF4EBP1 −/− hMSCs ( Fig.…”

Biomarkers of aging

“…The complexity of the SASP, typically appraised by a list of secreted proteins, has been largely underestimated, as a small handful of factors cannot explain this varying phenotype. In fact, many studies reported that expression of the SASP is subject to regulation by an intricate but well-ordered signaling network, which comprises but is not limited to ATM, γH2AX, Zscan4, TAK1, p38, MAPK, mTOR, IL-1α, NF-κB, c/EBPβ, JAK2/STAT3 and GATA4 (Borghesan et al, 2020;Hernandez-Segura et al, 2018;Song et al, 2020a;Song et al, 2020b;Sun et al, 2018b;Sun et al, 2022b). Despite these advances, increasing lines of data suggest that SASP regulation is indeed multilayered, including contributions from pre-transcriptional signaling cascades such as the cGAS-STING pathway, epigenetic factors governing DNA and histone modifications as well as the super-enhancer landscape in senescent cells (Criscione et al, 2016a;Glück et al, 2017;Sati et al, 2020;Tasdemir et al, 2016;Yang et al, 2017;Zhang et al, 2021a).…”

A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body

“…Since both aging and exercise involve distinct organs, tissues, and cell types, 4 , 6 , 21 , 22 , 23 , 24 a systemic and integrative study across multiple tissues, dissecting the molecular programs in tissue- and cell type-specific manner, is of critical importance. 25 , 26 , 27 , 28 , 29 In the past few years, high-throughput single-cell transcriptomes have been constructed for aging and its interventions, 30 , 31 , 32 such as caloric restriction and heterochronic parabiosis in mammalian species, 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 providing unprecedented resolution of the cellular and molecular changes in aged animals. However, whether and how exercise rewires the transcriptome at the systemic level, especially in aged animals, remains largely unexplored.…”