Metformin as a Tool to Target Aging Barzilai, Nir; Crandall, Jill P.; Kritchevsky, Stephen B. ...
Cell metabolism,
06/2016, Volume:
23, Issue:
6
Journal Article
Peer reviewed
Open access
Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against ...several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
Should you take the anti-diabetic drug metformin to slow down aging? Barzilai and colleagues would argue yes, making a case that aging and age-related diseases can be pharmacologically delayed, as they embark on the TAME (Targeting Aging with Metformin) clinical trial in 65- to 79-year-old people.
Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher ...mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.
2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.
Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73-1.00). There was no evidence for heterogeneity of effect (Cochran's Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71-0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72-1.00).
In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.
Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular ...senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.
A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.
Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).
Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases.
ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically ...relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
The Foundation for the National Institutes of Health Sarcopenia Project used data from nine sources of community-dwelling older persons: Age, Gene/Environment Susceptibility-Reykjavik Study, Boston Puerto Rican Health Study, a series of six clinical trials, Framingham Heart Study, Health, Aging, and Body Composition, Invecchiare in Chianti, Osteoporotic Fractures in Men Study, Rancho Bernardo Study, and Study of Osteoporotic Fractures. Feedback from conference attendees was obtained via surveys and breakout groups.
The pooled sample included 26,625 participants (57% women, mean age in men 75.2 ±6.1 SD and in women 78.6 ±5.9 years). Conference attendees emphasized the importance of evaluating the influence of body mass on cutpoints. Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 for men and <0.512 for women.
These evidence-based cutpoints, based on a large and diverse population, may help identify participants for clinical trials and should be evaluated among populations with high rates of functional limitations.
Objective The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. Background Frailty is common in the elderly and is associated with ...adverse health outcomes. Impact of frailty on HF risk is not known. Methods We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. Results Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). Conclusions Frailty is independently associated with risk of HF in older adults.
Age-related losses of lean mass and shifts to central adiposity are related to functional decline and may predict mortality and/or explain part of the risk of weight loss. To determine how mortality ...risk is related to shifts in body composition, changes should be considered in the context of overall weight change.
Five-year changes in body composition were assessed with computed tomography (cm2) and dual x-ray absorptiometry (kg) in 869 men and 934 women initially aged 70-79 years. All-cause mortality was monitored for up to 12 years (2002-2003 to September 30, 2014), and risk was assessed using sex-specific Cox models.
Both men and women lost weight, visceral fat area, thigh muscle area, lean mass, and fat mass (all p < .01) but gained intermuscular thigh fat area (p < .01). There were 995 deaths. After adjustment for total weight change, demographics, and chronic disease, losing thigh muscle area was associated with higher mortality in both men (1.21, 1.08-1.35) and women (1.18, 1.01-1.37, per 9.0cm2) and was especially strong in normal weight (body mass index < 25kg/m2) individuals and those losing weight. Losing intermuscular thigh fat was protective against mortality only in normal weight (0.66, 0.51-0.86) and weight stable men (0.79, 0.66-0.95, per 3.2cm2). Changes in visceral fat area were not associated with mortality.
Older adults with greater loss of thigh muscle than expected for overall weight change had a higher mortality risk compared to those with relative thigh muscle preservation, suggesting that conservation of muscle mass is important for survival in old age.
Objectives
The current Recommended Dietary Allowance (RDA) for protein is based on short‐term nitrogen balance studies in young adults and may underestimate the amount needed to optimally preserve ...physical function in older adults. We examined the association between protein intake and the onset of mobility limitation over 6 years of follow‐up in older adults in the Health ABC study.
Design
Prospective cohort study.
Setting
Memphis, Tennessee and Pittsburgh, Pennsylvania.
Participants
Community‐dwelling, initially well‐functioning adults aged 70–79 years (n = 1998).
Measurements
Protein intake (g/kg body weight/d) was calculated using an interviewer‐administered 108‐item food frequency questionnaire at baseline. Mobility limitation was assessed semi‐annually and defined as reporting any difficulty walking one‐quarter of a mile or climbing 10 steps on 2 consecutive 6‐month contacts. The association between protein intake and incident mobility limitation was examined using Cox proportional hazard regression models adjusting for demographics, behavioral characteristics, chronic conditions, total energy intake, and height.
Results
Mean (SD) protein intake was 0.91 (0.38) g/kg body weight/d, with 43% reporting intakes less than the RDA (0.8 g/kg body weight/d). During 6 years of follow‐up, 705 participants (35.3%) developed mobility limitations. Compared to participants in the upper tertile of protein intake (≥1.0 g/kg body weight/d), participants in the lower two tertiles of protein intake (<0.7 and 0.7 –<1.0 g/kg body weight/d) were at greater risk of developing mobility limitation over 6 years of follow‐up (RR (95% CI): 1.86 (1.41–2.44) and 1.49 (1.20–1.84), respectively).
Conclusion
Lower protein intake was associated with increased risk of mobility limitation in community‐dwelling, initially well‐functioning older adults. These results suggest that protein intakes of ≥1.0 g/kg body weight/d may be optimal for maintaining physical function in older adults.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots ...quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 women, p = 0.49 men). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
We investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed ...AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.
•Geriatric assessment, with a focus on cognitive and physical function, improves prediction of survival among older adults treated for AML.•Use of geriatric assessment may inform trial design and interventions to improve outcomes for older adults with AML.
Background/objectives
Poor appetite in older adults leads to sub‐optimal food intake and increases the risk of undernutrition. The impact of poor appetite on food intake in older adults is unknown. ...The aim of this study was to examine the differences in food intake among older community‐dwelling adults with different reported appetite levels.
Design
Cross‐sectional analysis of data from a longitudinal prospective study.
Setting
Health, aging, and body composition study performed in the USA.
Participants
2,597 community‐dwelling adults aged 70–79.
Measurements
A semi‐quantitative, interviewer‐administered, 108‐item food frequency questionnaire designed to estimate dietary intake. Poor appetite was defined as the report of a moderate, poor, or very poor appetite in the past month and was compared with good or very good appetite.
Results
The mean age of the study sample was 74.5 ± 2.8 years; 48.2% were men, 37.7% were black, and 21.8% reported a poor appetite. After adjustment for total energy intake and potential confounders (including biting/chewing problems), participants with a poor appetite had a significantly lower consumption of protein and dietary fiber, solid foods, protein rich foods, whole grains, fruits, and vegetables, but a higher consumption of dairy foods, fats, oils, sweets, and sodas compared to participants with very good appetite. In addition, they were less likely to report consumption of significant larger portion sizes.
Conclusion
Older adults reporting a poor appetite showed a different dietary intake pattern compared to those with (very) good appetite. Better understanding of the specific dietary intake pattern related to a poor appetite in older adults can be used for nutrition interventions to enhance food intake, diet variety, and diet quality.
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