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

Aging is the largest risk factor for most pathologies, ranging from cancer to neurodegenerative disorders. Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause pathological manifestations, with senescence as a defining feature of myriad aging-related diseases. Senescent cells display hallmark features, including the senescence-associated secretory phenotype (SASP), a major driver of pathologies, and alterations to the structure and function of organelles. Targeted elimination of senescent cells has emerged as a promising therapeutic solution to ameliorate tissue damage and promote repair and regeneration. In the scope of clinical medicine, advances that identify key biochemical pathways, specifically those differentiating senescent cells from their proliferating counterparts, would positively affect pathological and aging processes. 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. 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. a course of progressive decline in physical, and often mental, capacities, often considered as adaptation to wear and tear. a cell state characterized by a stable and usually irreversible cell cycle arrest in response to different types of stress and/or damage, including cell replicative exhaustion, oxidative stress, oncogene activation, and therapeutic agents. fragments that pinch off from intact nuclei of primary cells during senescence, can activate the innate immunity cytosolic DNA-sensing pathway, and lead to short-term or chronic inflammation. a cell response to agents that cause single and/or double strand breaks of DNA, with activation of a network of intracellular pathways that sense, signal, and repair DNA lesions in the nucleus. a period of good health in an individual’s lifetime. the longest period over which the life of any organism or species may extend. changes in metabolic pathways that alter the bio-energetic profile and metabolism of the cell, including anabolism and catabolism. a condition in which the regulation of mitochondrial homeostasis, production of mitochondrial metabolites, membrane potential, and ROS generation is compromised. Mitochondrial dysfunction can decrease the NAD+/NADH ratio and induce a senescent phenotype overlapping yet differing from that caused by other senescence inducers. a subtype of cellular senescence induced by aberrant activation of a specific oncogene such as HRASG12V, which causes cell hyperproliferation followed by subsequent proliferation arrest. a subtype of senescence playing proregenerative or morphogenetic roles in physiological events such as embryogenesis, wound healing, and limb regeneration. It can promote cell turnover, tissue remodeling, and, paradoxically, growth. a failure of protein homeostasis caused by accumulation of misfolded proteins within the cell, which eventually compromise cellular function. a subtype of senescence induced by telomeric attrition after multiple cell divisions, with a decrease in cell proliferative potential. It may serve as one of the major safeguards to maintain cellular integrity necessitated by the extended longevity of humans. the set of protein factors secreted by cells into the extracellular space. Once used for senescent cells, it is also referred to as the SASP. enhanced lysosomal enzymatic activity usually observed in senescent cells, a feature that allows increased hydrolysis of β-galactoside into monosaccharides. It is frequently used as a biomarker for detection of cellular senescence. a hallmark feature of senescent cells, characterized by robust production and secretion of soluble molecules such as growth factors, cytokines, chemokines, and extracellular matrix metalloproteases. a group of chemical compounds or phytochemicals that are applied to selectively eliminate senescent cells via induction of programmed cell death. a subtype of senescence that appears after exposure of cells to a chemical or physical stimulation that induces oxidative stress, DNA damage, and/or mitochondrial injury. a subtype of cellular senescence triggered by therapeutic modalities such as chemotherapy and radiotherapy.