Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases

Abstract

Aging is a major risk factor for numerous human pathologies, including cardiovascular, metabolic, musculoskeletal, and neurodegenerative conditions and various malignancies. While our understanding of aging is far from complete, recent advances suggest that targeting fundamental aging processes can delay, prevent, or alleviate age-related disorders. Cellular senescence is physiologically beneficial in several contexts, but it has causal roles in multiple chronic diseases. New studies have illustrated the promising feasibility and safety to selectively ablate senescent cells from tissues, a therapeutic modality that holds potential for treating multiple chronic pathologies and extending human healthspan. Here, we review molecular links between cellular senescence and age-associated complications and highlight novel therapeutic avenues that may be exploited to target senescent cells in future geriatric medicine.

Keywords: SASP; cellular senescence; clinical trials; geroscience; senolytics.

Figure 1.. The Hallmarks of Organismal Aging.

Organismal aging (center) is a complex process contributing to progressive decline of organ functionality and regenerative potential of tissues. The aging clock is governed by interconnected hallmarks of organismal aging. Understanding how the underlying biological mechanisms of aging correlate with and impact longitudinal changes in health trajectories might offer an opportunity to identify resilience mechanisms, their dynamic changes, and their impact on physiological integrity. In geroscience, a research field that is rapidly progressing in the current era of precision medicine, novel antiaging agents developed to delay organismal aging will significantly rely on their safety and effectiveness at the level of cells, basic biological units of an individual (outside the circle).

Figure 2.. Hallmarks of Cellular Senescence.

Distinct alterations in molecular pathways of cellular senescence result in morphological changes. Senescent cells are enlarged, flattened, and have an irregular cell shape (not shown). Their nuclear integrity is compromised due to the loss of lamin B1 and exclusion of the high mobility group protein B1 (HMGB1), accompanied by the emergence of cytoplasmic chromatin fragments (CCFs). Senescent cells have increased lysosomal content, as manifested by elevated β-galactosidase (SA-β-gal) activity, with an increased number of large but dysfunctional mitochondria that produce high levels of reactive oxygen species (ROS). There is usually an enhanced level of lipofuscin in the cytoplasm and upregulation of p16^INK4a/p21^CIP1 in the nucleus. Biosynthesis and extracellular secretion of a large number of proinflammatory and proapoptotic factors [senescence-associated secretory phenotype (SASP)] is robust and constitutes one of the major features of senescent cells. Yellow arrows: signal transduction or molecular traffic; purple arrows: DNA fragment transportation; white arrows: up- or downregulation of expression or activities. Red text: representative typical hallmarks of senescent cells. Different colors of the outlines of SASP factors indicate various types of secreted molecules (e.g., cytokines, chemokines, and growth factors). Abbreviations: DDR, DNA damage response; MMP, matrix metalloproteinase; PTM, post-translational modification.

Figure 3.. Therapeutic Strategies That Can Be Exploited to Target Senescent Cells.

Aging is the leading risk factor for many chronic diseases, including but not limited to cancers, metabolic syndrome, and musculoskeletal, cardiovascular, and neurodegenerative disorders. Recent studies suggest that targeting fundamental aging mechanisms may be a better solution than targeting each chronic pathology individually in order to increase healthspan and delay multimorbidity. Pilot efforts have recently been made to therapeutically target cellular senescence, including selectively eliminating senescent cells by inducing their passive apoptosis (senolytic treatment) (A), and modulating the senescence-associated secretory phenotype (SASP) (SASP suppression, or senostatics) by blocking the SASP development or interfering with the function of its key components in the tissue microenvironment (B). In each figure, yellow arrows represent stimulating or promotive actions, while red arrows are suppressive or counteractive. Agents within yellow or orange boxes are exemplifying senolytics (A) and SASP inhibitors (B), respectively. Abbreviations: AMPK, AMP-activated protein kinase; OXR1, oxidation resistance 1; ROS, reactive oxygen species.