Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved. Show more

Long-term disorders are the main challenge facing health-care systems worldwide, but health systems are largely configured for individual diseases rather than multimorbidity. We examined the distribution of multimorbidity, and of comorbidity of physical and mental health disorders, in relation to age and socioeconomic deprivation. In a cross-sectional study we extracted data on 40 morbidities from a database of 1,751,841 people registered with 314 medical practices in Scotland as of March, 2007. We analysed the data according to the number of morbidities, disorder type (physical or mental), sex, age, and socioeconomic status. We defined multimorbidity as the presence of two or more disorders. 42·2% (95% CI 42·1-42·3) of all patients had one or more morbidities, and 23·2% (23·08-23·21) were multimorbid. Although the prevalence of multimorbidity increased substantially with age and was present in most people aged 65 years and older, the absolute number of people with multimorbidity was higher in those younger than 65 years (210,500 vs 194,996). Onset of multimorbidity occurred 10-15 years earlier in people living in the most deprived areas compared with the most affluent, with socioeconomic deprivation particularly associated with multimorbidity that included mental health disorders (prevalence of both physical and mental health disorder 11·0%, 95% CI 10·9-11·2% in most deprived area vs 5·9%, 5·8%-6·0% in least deprived). The presence of a mental health disorder increased as the number of physical morbidities increased (adjusted odds ratio 6·74, 95% CI 6·59-6·90 for five or more disorders vs 1·95, 1·93-1·98 for one disorder), and was much greater in more deprived than in less deprived people (2·28, 2·21-2·32 vs 1·08, 1·05-1·11). Our findings challenge the single-disease framework by which most health care, medical research, and medical education is configured. A complementary strategy is needed, supporting generalist clinicians to provide personalised, comprehensive continuity of care, especially in socioeconomically deprived areas. Scottish Government Chief Scientist Office. Copyright © 2012 Elsevier Ltd. All rights reserved. Show more

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression. Show more