p21 induces a senescence program and skeletal muscle dysfunction.

Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.

Characterization of cellular senescence in aging skeletal muscle.

Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.

Exercise reduces circulating biomarkers of cellular senescence in humans.

Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Three Medicolegal Cases of Searching for the Stone: Lessons Learned Along the Journey.

We present three medicolegal cases of medical negligence settled out of court. These cases all involved patients who presented to the emergency department (ED) with a suspected diagnosis of kidney stone. Highlighted are the importance of patient communication, addressing incidental findings found during a patient's ED visit, anticipating complications, and the need for thorough documentation.

Harnessing the effects of endurance exercise to optimize cognitive health: Fundamental insights from Dr. Mark P. Mattson.

Dr. Mark Mattson has had a highly productive and impactful tenure as a neuroscientist at the Intramural Research Program of the National Institute on Aging. He has made notable contributions to understanding the mechanisms by which energetic stress, imparted by behaviors such as physical activity and periods of fasting, promotes rejuvenation and resilience within brain regions critical for learning and memory. In honor of Dr. Mattson's work, this manuscript will highlight the fascinating mechanisms by which endurance exercise training conveys beneficial effects upon the structure and function of the nervous system; that is, by mediating the synthesis and secretion of factors that directly support brain homeostasis, including brain-derived neurotrophic factor, FNDC5/irisin, ketone bodies, growth factors, cathepsin B, serotonin, and 4-hydroxynonenal. The molecular and cellular effects of these factors are discussed herein. In the face of population aging and an overwhelming surge in the prevalence of Alzheimer's disease and related disorders, Dr. Mattson's work as a champion and role model for physically active lifestyles is more important than ever.