Isolation of Nuclei from Human Intermuscular Adipose Tissue and Downstream Single-Nuclei RNA Sequencing.

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types.

Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort.

Machine learning models are increasingly being used to estimate "brain age" from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

Validation of biomarkers of aging.

The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.

Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial.

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 ±â€…5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost -10.8 ±â€…0.9 kg (-11.3% ±â€…5.4%) over 18 weeks compared with +0.5 ±â€…0.9 kg (+0.03% ±â€…3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F = 4.17, p ≤ .05) and associated with the degree of weight loss (R2 = 0.12, p ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions.

Association of a Blood-Based Aging Biomarker Index With Death and Chronic Disease: Cardiovascular Health Study.

BACKGROUND: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration. METHODS: A biomarker index (BI) was constructed in the Cardiovascular Health Study (N = 3 197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up. RESULTS: The hazard ratio (HR, 95% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7% and 22.0% in women and men, respectively. CONCLUSIONS: Biomarker index was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.

Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

Objective: Examine the association of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. Methods: Cross-sectional data from 829 older adults ≥70 years was used. Total abdominal, subcutaneous, and visceral AT; and thigh muscle fat infiltration (MFI) was quantified by MRI. SM mitochondrial energetics were characterized using in vivo 31 P-MRS (ATP max ) and ex vivo high-resolution respirometry (maximal oxidative phosphorylation (OXPHOS)). ActivPal was used to measure PA (step count). Linear regression models adjusted for covariates were applied, with sequential adjustment for BMI and PA. Results: Independent of BMI, total abdominal (standardized (Std.) ß=-0.21; R 2 =0.09) and visceral AT (Std. ß=-0.16; R 2 =0.09) were associated with ATP max ( p <0.01), but not after further adjustment for PA (p≥0.05). Visceral AT (Std. ß=-0.16; R 2 =0.25) and thigh MFI (Std. ß=-0.11; R 2 =0.24) were negatively associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA ( p <0.05). Total abdominal AT (Std. ß=-0.19; R 2 =0.24) and visceral AT (Std. ß=-0.17; R 2 =0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p<0.05). Conclusions: Skeletal MFI and abdominal visceral, but not subcutaneous AT, are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

Strategies to reduce the onset of sleeve gastrectomy associated bone loss (STRONG BONES): Trial design and methods.

Background: Despite recognized improvements in obesity-related comorbidities, mounting evidence implicates surgical weight loss in the onset of skeletal fragility. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure and is associated with 3-7% axial bone loss in the year following surgery. Bisphosphonates are FDA-approved medications for the prevention and treatment of age-related bone loss and may represent a strategy to reduce bone loss following SG surgery. Methods: The Strategies to Reduce the Onset of Sleeve Gastrectomy Associated Bone Loss (STRONG BONES) trial (NCT04922333) is designed to definitively test whether monthly administration of the bisphosphonate, risedronate, for six months can effectively counter SG-associated bone loss. Approximately 120 middle-aged and older (≥40 years) SG patients will be randomized to six months of risedronate or placebo treatment, with skeletal outcomes assessed at baseline, six, and 12-months post-surgery. The primary outcome of the trial is 12-month change in total hip areal bone mineral density (aBMD), measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and quantitative computed tomography (QCT) derived changes in bone quality. Change in muscle mass and function will also be assessed, as well as biomarkers of bone health, turnover, and crosstalk, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Discussion: Results from the STRONG BONES trial have the potential to influence current clinical practice by determining the ability of bisphosphonate use to mitigate bone loss and concomitant fracture risk in middle-aged and older SG patients.

Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design.

Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported. Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15 (p = 0.05), and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c (p = 0.03). This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.

Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review.

The Wake Forest nonhuman primate (NHP) Radiation Late Effects Cohort (RLEC) is a unique and irreplaceable population of aging NHP radiation survivors which serves the nation's need to understand the late effects of radiation exposure. Over the past 16 years, Wake Forest has evaluated > 250 previously irradiated rhesus macaques (Macaca mulatta) that were exposed to single total body irradiation (IR) doses of 1.14-8.5 Gy or to partial body exposures of up to 10 Gy (5% bone marrow sparing) or 10.75 Gy (whole thorax). Though primarily used to examine IR effects on disease-specific processes or to develop radiation countermeasures, this resource provides insights on resilience across physiologic systems and its relationship with biological aging. Exposure to IR has well documented deleterious effects on health, but the late effects of IR are highly variable. Some animals exhibit multimorbidity and accumulated health deficits, whereas others remain relatively resilient years after exposure to total body IR. This provides an opportunity to evaluate biological aging at the nexus of resilient/vulnerable responses to a stressor. Consideration of inter-individual differences in response to this stressor can inform individualized strategies to manage late effects of radiation exposure, and provide insight into mechanisms underlying systemic resilience and aging. The utility of this cohort for age-related research questions was summarized at the 2022 Trans-NIH Geroscience Interest Group's Workshop on Animal Models for Geroscience. We present a brief review of radiation injury and its relationship to aging and resilience in NHPs with a focus on the RLEC.

An Examination of Whether Diabetes Control and Treatments Are Associated With Change in Frailty Index Across 8 Years: An Ancillary Exploratory Study From the Action for Health in Diabetes (Look AHEAD) Trial.

OBJECTIVE: The aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging. RESEARCH DESIGN AND METHODS: We conducted exploratory analyses from 4,169 participants, aged 45-76 years, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up. RESULTS: Baseline and average HbA1c levels over time of <7%, as compared with ≥8%, were associated with less increase in FI scores over 8 years (both P ≤ 0.002). After adjustment for HbA1c, use of metformin and weight loss >5% were independently associated with slower increases in frailty. CONCLUSIONS: Lower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging?

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

Research priorities for measuring biologic age: summary and future directions from the Research Centers Collaborative Network Workshop.

Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Analysis of Epigenetic Age Acceleration and Healthy Longevity Among Older US Women.

Importance: Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality. Objective: We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women. Design, Setting, and Participants: This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021. Exposures: EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim. Main Outcomes and Measures: Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years. Results: Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72; P < .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98; P = .03) compared with women who did not survive to age 90 years. Conclusions and Relevance: These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans.

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans. METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q). FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence. INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials. FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

Psychosocial stress increases risk for type 2 diabetes in female cynomolgus macaques consuming a western diet.

Chronic psychosocial stress is associated with increased risk of many chronic diseases including type 2 diabetes mellitus. However, it is difficult to establish a causal relationship between stress and diabetes in human studies because stressors often are self-reported and may be distant in time from metabolic consequences. Macaques are useful models of the effects of chronic psychosocial stress on health and may develop obesity and diabetes similar to human beings. Thus, we studied the relationships between social subordination stress - a well-validated psychological stressor in macaques - and body composition and carbohydrate metabolism in socially housed, middle-aged female cynomolgus monkeys (Macaca fascicularis; n = 42). Following an 8-week baseline phase, the monkeys were fed a Western diet for 36 months (about equivalent to 10 human years). Social status was determined based on the outcomes of agonistic interactions (X¯= 33.3 observation hours/monkey). Phenotypes collected included plasma cortisol, body composition, circulating markers of glucose metabolism, activity levels, and heart rate variability measured as RMSSD (root of mean square of successive differences) and SDDN (standard deviation of beat to beat interval) after 1.5- and 3-years on diet. Mixed model analyses of variance revealed that aggression received, submissions sent, and cortisol were higher, and RMSSD and SDNN were lower in subordinates than dominants (social status: p < 0.05). After 3 years of Western diet consumption, fasting triglyceride, glucose and insulin concentrations, calculated insulin resistance (HOMA-IR), body weight and body fat mass increased in all animals (time: all p's < 0.05); however, the increase in fasting glucose and HOMA-IR was significantly greater in subordinates than dominants (time x social status: p's < 0.05). Impaired glucose metabolism, (glucose > 100 mg/dl) incidence was significantly higher in subordinates (23%) than dominants (0%) (Fisher's exact test, p < 0.05). These findings suggest that chronic psychosocial stress, on a Western diet background, significantly increases type 2 diabetes risk in middle-aged female primates.

Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction.

Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m2. Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (- 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (- 0.28 [Formula: see text] 0.59 points, p = [Formula: see text]), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all [Formula: see text] s = between - 0.21 and - 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] s = - 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance.

Lifelong physical activity attenuates age- and Western-style diet-related declines in physical function and adverse changes in skeletal muscle mass and inflammation.

It is unknown if consumption of a Western diet (WD; high-fat/sucrose), versus a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary activity attenuates age- and WD-associated declines in function. Accordingly, we studied 4 cohorts of mice that consumed either normal chow [NC] or WD with or without access (sedentary, Sed) to voluntary wheel running [VWR] beginning at 3 mo of age. We assessed coordination, grip strength and endurance every 6 mo throughout life, and measured skeletal muscle mass and inflammation at 3 pre-determined ages (6-7, 13-14 and 19-20 mo). Age-related declines (% change 3-18 mo) in physical function were accelerated in WD-Sed versus NC-Sed (coordination: +47 ± 5%; grip strength: +18 ± 2%; endurance: +32 ± 5%; all p < 0.05). VWR attenuated declines in physical function within diet group (coordination: -31 ± 3% with WD-VWR; -18 ± 2% with NC-VWR; grip strength: -26 ± 2% with WD-VWR; -24 ± 2% with NC-VWR; endurance: -48 ± 4% with WD-VWR; -23 ± 6% with NC-VWR; all p < 0.05). Skeletal muscle mass loss and pro-inflammatory cytokine abundance were exacerbated by WD throughout life (mass: NC-Sed [-]7-28%, WD-Sed [-]17-40%; inflammation: NC-Sed [+]40-65%, WD-Sed [+]40-84%, all p < 0.05 versus NC-Sed), and attenuated by VWR (mass: NC-VWR, [-]0-10%, WD-VWR [-]0-10%; inflammation: NC-VWR [+]0-30%, WD-VWR [+]0-42%, all p < 0.05 versus diet-matched Sed group). Our results depict the temporal impairment of physical function over the lifespan in mice, acceleration of dysfunction with WD, the protective effects of voluntary exercise, and the potential associations with skeletal muscle mass and inflammation.