Atkinson, Elizabeth J.

Abstract Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Abstract Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500

AbstractA robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age‐related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow‐up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c‐statistic for risk of death (0.79, 95% confidence interval (CI): 0.76–0.82) than the covariates alone (0.70, CI: 0.67–0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Abstract Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None. Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p &lt;0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p&lt;0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index. Presentation: Friday, June 16, 2023