Citations

Abstract Senescent cells drive age-related tissue dysfunction through their potent secretome, termed the senescence associated secretory phenotype (SASP). Circulating concentrations of SASP factors may reflect biological age and serve as clinically useful biomarkers of surgical risk and ultimately, surrogate endpoints in clinical trials. However, they remain largely uncharacterized. We tested associations between circulating concentrations of SASP proteins and biological age, as determined by the accumulation of age-related health deficits, and/or postoperative outcomes in a sample of residents in Olmstead County, MN, age 60-90 years (n = 115) and cohorts of older adults undergoing surgery for severe aortic stenosis (prospective; n = 97) or ovarian cancer (case-control; n = 36). Circulating concentrations of SASP factors were associated with biological age and adverse postoperative outcomes, including risk of any adverse event or rehospitalization within the year following surgery (aortic stenosis group) or admission to an intensive care unit within 30 days of hospital discharge (ovarian cancer group). Gradient boosting machine modeling revealed a panel of SASP factors that predicted adverse outcomes across both surgical groups better than biological age or chronological age and sex. This suggests that the circulating SASP is a robust indicator of age-related health status and may help guide clinical decision making. Furthermore, circulating SASP factors may be harnessed as a readily quantifiable biomarkers in senescence-targeting interventional human studies.

Abstract Diverse forms of molecular and cellular stress trigger senescence, a state of growth arrest in proliferation-competent cells that is often accompanied by a robust secretory phenotype. Senescent cell burden increases with age in multiple tissues and, plausibly, contributes to the pathogenesis of age-related diseases and geriatric syndromes. Discovery science efforts have identified druggable targets in senescent cells, including key nodes in anti-apoptosis pathways, that distinguish them from non-senescent counterparts and enable pharmacological approaches for their selective elimination. The therapeutic potential of senolytic interventions to improve health- and lifespan has been supported by translational research studies, including murine models of aging, atherosclerosis, osteoporosis, neurodegeneration, pulmonary fibrosis, and frailty. These studies have informed the design of first-in-human clinical trials of senolytic drugs, which have recently begun. The objective of this lecture is to highlight both the progress and challenges of advancing interventions targeting senescent cells from bench to bedside.

Leigh syndrome embodies degenerative disorders with a collection of symptoms secondary to inborn errors of metabolism. Combinations of hypomorphic and loss‐of‐function alleles in many genes have been shown to result in Leigh syndrome. Interestingly, deficiency for the tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH) can lead to Leigh‐like syndrome in some circumstances and to cancer (paraganglioma, renal cell carcinoma, gastrointestinal stromal tumor) in others. In our experiments originally intended to create an inducible whole‐body SDH‐loss mouse model of tumorigenesis, we generated a condition reminiscent of Leigh‐like syndrome that is lethal to mice within 4 wk. Remarkably, as has been shown for other mitochondrial diseases, chronic hypoxia offers substantial protection to mice from this condition after systemic SDH loss, allowing survival in the context of profoundly impaired oxidative metabolism.—Al Khazal, F., Holte, M. N., Bolon, B., White, T. A., LeBrasseur, N., Maher, L. J. III. A conditional mouse model of complex II deficiency manifesting as Leigh‐like syndrome. FASEB J. 33, 13189–13201 (2019). www.fasebj.org

AbstractAging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time‐restricted feeding (TRF) benefit multiple health parameters when initiated in early life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet‐induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)–induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

Abstract Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16 Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.