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Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of [p21.sup.+] cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of [p21.sup.+] cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, [p21.sup.+] cell clearance did not alter bone loss due to aging; conversely, [p16.sup.+] cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, [p21.sup.+] neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while [p21.sup.+] OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was [p21.sup.+] and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of [p21.sup.+] versus [p16.sup.+] senescent/ senescent-like cells that may be leveraged for therapeutic opportunities., Introduction At the cellular level, aging is characterized by several hallmarks, including cellular senescence (1), which is driven by an increase in the cyclin-dependent kinase inhibitors Cdknla (p21) and/or Cdknla [...]

Circadian rhythm disruption (CD) is associated with impaired glucose homeostasis and type 2 diabetes mellitus (T2DM). While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates metabolic dysfunction. Here, we used an approach encompassing analysis of behavioral, physiological, transcriptomic, and epigenomic effects of CD and consequences of restoring fasting/feeding cycles through time-restricted feeding (tRF) in mice. Results show that CD perturbs glucose homeostasis through disruption of pancreatic β cell function and loss of circadian transcriptional and epigenetic identity. In contrast, restoration of fasting/feeding cycle prevented CD-mediated dysfunction by reestablishing circadian regulation of glucose tolerance, β cell function, transcriptional profile, and reestablishment of proline and acidic amino acid–rich basic leucine zipper (PAR bZIP) transcription factor DBP expression/activity. This study provides mechanistic insights into circadian regulation of β cell function and corresponding beneficial effects of tRF in prevention of T2DM.

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

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 p16Ink4a 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.

RationaleFrailty represents an increased vulnerability to adverse health outcomes. The frailty phenotype conceptual model (three or more patient attributes of wasting, exhaustion, low activity, slowness, and weakness) is associated with increased morbidity and mortality in geriatric populations.ObjectivesOur objective was to describe the risks associated with frailty in patients with chronic obstructive pulmonary disease.MethodsData from the National Emphysema Treatment Trial (NETT) were retrospectively analyzed. The frailty phenotype conceptual model was operationalized as three or more frailty parameters (a body mass index decrease of ≥5% over 12 months, self-reported exhaustion, low 6-minute walk distance, or physical activity or respiratory muscle strength in the lowest quartile). Frail participants were compared with participants with two or fewer frailty parameters. Participants were followed starting 12 months after NETT randomization (to minimize surgical effect) for 24 months. Univariate, multivariate, Kaplan-Meier, and Cox proportional hazard analyses were performed, adjusting for treatment arm, age, modified Medical Research Council dyspnea scale, sex, and baseline forced expiratory volume in 1 second (FEV1). Multiple imputation was used for missing values.ResultsThe participants (N = 902) were predominantly white (94.5%) males (59.5%), with a median age of 67 years (interquartile range, 63-70 yr) and a median FEV1% predicted of 26 (interquartile range, 20-33). Six percent of the participants (95% confidence interval [CI], 4.5 to 7.6) were frail. The incidence rate of frailty was 6.4 per 100 person-years. Frail participants reported significantly worse disease-specific and overall quality of life by St. George's Respiratory Questionnaire total score (mean difference of 11.6; 95% CI, 7.6 to 15.6; P < 0.001), mental composite on Medical Outcomes Survey Short Form-36 (mean difference -6.8; 95% CI, -10.0 to -3.6; P < 0.001), and physical composite scores on Medical Outcomes Survey Short Form-36 (mean difference -16.7; 95% CI, -21.3 to -12.1; P = 0.001). Frail participants had an increased rate of hospitalization (adjusted hazard ratio, 1.6; 95% CI, 1.1 to 2.5; P = 0.02) and an adjusted increase in hospital use of 8.0 days (95% CI, 4.4 to 11.6; P < 0.001) compared with nonfrail participants. Frail participants had a higher mortality rate (adjusted hazard ratio, 1.4; 95% CI, 0.97 to 2.0; P = 0.07).ConclusionsAmong adults with chronic obstructive pulmonary disease, our measure of frailty (modified from the Fried frailty phenotype) was associated with incident and longer-duration hospitalization, and with poor quality of life.

Cellular senescence is a biological mechanism of aging and age‐related diseases. The aim of this study was to examine whether senescence biomarkers are associated with frailty and physical function trajectories in patients undergoing kidney transplantation (KT). We also discussed the relationship between senescence biomarkers and KT function. In this multicenter study, we prospectively assessed plasma levels of senescence biomarkers, frailty as measured by the Physical Frailty Phenotype, and physical function as measured by the Short Physical Performance Battery prior to KT. Frailty, physical function, and KT function were also measured 1 year after KT. Variable associations were assessed using Cox and relaxed least absolute shrinkage and selection operation regression. The cohort consisted of 197 participants (mean age 53 ± 13 years, 61.4% male, and 80.2% White race). Higher pre‐KT levels of macrophage‐derived chemokine (MDC/CCL22) and growth differentiation factor‐15 (GDF‐15) were independently associated with less improvement in frailty and/or physical function during the first year after KT. Higher pre‐KT levels tumor necrosis factor receptor superfamily member 6 (FAS) and MMP‐9 levels were independently associated with lower KT function one year after KT. Pre‐KT cellular senescence may contribute to frailty, physical function, and kidney function trajectories during the first year after KT. [ABSTRACT FROM AUTHOR]

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging., Introduction The aging population and life expectancy continue to increase (1), and while unlikely to reverse course, this trend of more people living longer creates challenges that society remains poorly [...]

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. The ESCRT components Vps4 and Hrs have previously been implicated in cholesterol homeostasis; thus, these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis. [ABSTRACT FROM AUTHOR]

Performance‐based measures of frailty are associated with healthcare utilization after kidney transplantation (KT) but require in‐person assessment. A promising alternative is self‐reported frailty. The goal of this study was to examine the ability of performance‐based and self‐reported frailty measures to predict 30‐day rehospitalizations after KT. We conducted a prospective, observational cohort study involving 272 adults undergoing KT at Mayo Clinic in Minnesota, Florida, or Arizona. We simultaneously measured frailty before KT using the physical frailty phenotype (PFP), the short physical performance battery (SPPB), and self‐report (the Patient‐Reported Outcomes Measurement Information System [PROMIS] 4‐item physical function short form v2.0). Both the PFP and self‐reported frailty were independently associated with more than a 2‐fold greater odds of 30‐day rehospitalizations, while the SPPB was not. To our knowledge, this is the first study to assess the prognostic value of all three of the above frailty measures in patients undergoing KT. The PFP is more prognostic than the SPPB when assessing the risk of 30‐day rehospitalizations; self‐reported frailty can complement the PFP but not replace it. However, the 4‐item survey assessing self‐reported frailty represents a simple way to identify patients undergoing KT surgery who would benefit from interventions to lower the risk of rehospitalizations. [ABSTRACT FROM AUTHOR]

It has long been known that aging, at both the cellular and organismal levels, contributes to the development and progression of the pathology of many chronic diseases. However, much less research has examined the inverse relationship-the contribution of chronic diseases and their treatments to the progression of aging-related phenotypes. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatments on aging, putative mechanisms by which these effects are mediated, and the open questions and future research directions required to understand the relationships between these diseases and aging.