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OBJECTIVEThe 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 METHODSWe 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.RESULTSBaseline and average HbA1c levels over time of 5% were independently associated with slower increases in frailty.CONCLUSIONSLower 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.

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, ages 45-76, 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 >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.

BACKGROUND: There is growing interest in identifying factors associated with healthy aging. This cross-sectional study evaluated associations of psychological resilience with factors associated with aging in older adults with type 2 diabetes mellitus (T2DM). METHODS: Participants were 3199 adults (72.2 ± 6.2 years of age, 61% female, 61% White, body mass index [BMI] = 34.2 ± 8.2 kg/m(2)) with T2DM enrolled in Look AHEAD (a multi-site randomized clinical trial comparing an intensive lifestyle intervention for weight loss to diabetes education and support). Participants were followed observationally after the 10-year intervention was discontinued. The following items were assessed approximately 14.4 years post-randomization in a cross-sectional analysis: Brief Resilience Scale; overnight hospitalizations in past year; physical functioning measured objectively (gait speed, grip strength) and via self-report (Pepper Assessment Tool for Disability; physical quality of life [QOL; SF-36]); a measure of phenotypic frailty based on having ≥3 of unintentional weight loss, low energy, slow gait, reduced grip strength, and physical inactivity. Depressive symptoms (PHQ-9) and mental QOL (SF-36) were also measured. Logistic/linear/multinomial regression was used to evaluate the association of variables with resilience adjusted for age, race/ethnicity, and gender. RESULTS: Greater psychological resilience was associated with lower BMI, fewer hospitalizations, better physical functioning (i.e., lower self-reported disability, better physical QOL, faster gait speed, greater grip strength, lower likelihood of frailty), fewer depressive symptoms, and greater mental QOL (all p < 0.05). Psychological resilience moderated the relationship of number of hospitalizations in the past year with self-reported disability and grip strength. CONCLUSIONS: Psychological resilience is associated with better physical function and QOL among older adults. Results should be interpreted cautiously given cross-sectional nature of analyses. Exploring the clinical benefits of resilience is consistent with efforts to shift the narrative on aging beyond “loss and decline” to highlight opportunities to facilitate healthy aging.

Background Individuals are often counseled to use behavioral weight loss strategies to reduce risk for cardiovascular disease (CVD). We examined whether any benefits for CVD risk from weight loss intervention extend uniformly to individuals across a range of underlying health states. Methods The time until first occurrence of a composite of fatal and nonfatal myocardial infarction and stroke, hospitalized angina, or CVD death was analyzed from 8 to 11 years of follow-up of 4,859 adults who were overweight or obese, aged 45–76 years with Type 2 diabetes. Individuals had been randomly assigned to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Participants were grouped by intervention assignment and a frailty index (FI) based on deficit accumulation, ordered from fewer (first tertile) to more (third tertile) deficits. Results Baseline FI scores were unrelated to intervention-induced weight losses and increased physical activity. The relative effectiveness of ILI on CVD incidence was inversely related to baseline FI in a graded fashion (p = .01), with relative benefit (hazard ratio = 0.73 [95% CI 0.55,0.98]) for individuals in the first FI tertile to no benefit (hazard ratio = 1.15 [0.94,1.42]) among those in the third FI tertile. This graded relationship was not seen for individuals ordered by age tertile (p = .52), and was stronger among participants aged 45–59 years (three-way interaction p = .04). Conclusions In overweight/obese adults with diabetes, multidomain lifestyle interventions may be most effective in reducing CVD if administered before individuals have accrued many age-related health deficits. However, these exploratory analyses require confirmation by other studies. Clinical Trial Registration NCT00017953

Background Indices of multimorbidity and deficit accumulation (ie, frailty indices) have been proposed as markers of biological aging. If true, changes in these indices over time should predict downstream changes in cognition and physical function, and mortality. Methods We examined associations that 8-year changes in (i) a multimorbidity index comprised of 9 chronic diseases and (ii) a frailty index (FI) based on deficit accumulation in functional, behavioral, and clinical characteristics had with subsequent measures of cognitive and physical function over 10 years. We drew data from 3 842 participants in the Action for Health in Diabetes clinical trial. They were aged 45–76 years at baseline and at risk for accelerated biological aging due to overweight/obesity and type 2 diabetes mellitus. Results A total of 1 501 (39%) of the cohort had 8-year increases of 1 among the 9 diseases tracked in the multimorbidity index and 868 (23%) had increases of ≥2. Those with greatest increases in multimorbidity tended to be older individuals, males, and non-Hispanic Whites. Greater FI increases tended to occur among individuals who were older, non-Hispanic White, heavier, and who had more baseline morbidities. Changes in multimorbidity and FI were moderately correlated (r = 0.26; p < .001). Increases in both multimorbidity and FI were associated with subsequently poorer composite cognitive function and 400-m walk speed and increased risk for death (all p < .001). Conclusions Accelerated biological aging, as captured by multimorbidity and frailty indices, predicts subsequent reduced function and mortality. Whether intensive lifestyle interventions generally targeting multimorbidity and FI reduce risks for downstream outcomes remains to be seen. Clinical Trials Registration Number: NCT00017953

Aims To assess whether there is an opportune window when intensive lifestyle intervention (ILI) benefits cognitive function. Methods Standardized cognitive assessments were collected following ≥8 years of either ILI or a control condition of diabetes support and education (DSE) in 3708 individuals, ages 45-76 years at enrollment, with type 2 diabetes and overweight or obesity. Frailty index (FI) scores were used to group individuals at baseline into tertiles according to their age-related health status. Linear models were used to describe intervention adherence and cognitive function, with interaction terms to examine the consistency of relationships among tertiles. Results Worse baseline FI scores were associated with poorer subsequent performance in tests of attention, processing speed, and executive function. No differences in any measure of cognitive function were observed between intervention groups within any FI tertile (all p > 0.10). Among individuals with worse baseline FI scores, weight gain was associated with poorer global cognitive function among participants assigned to DSE. There was no association between weight changes and cognitive function among participants assigned to ILI. Conclusions Among adults with type 2 diabetes and overweight/obesity, we found no evidence that there is a window of opportunity based on FI when ILI benefits cognitive function.

Background/objectives Type 2 diabetes mellitus and obesity are sometimes described as conditions that accelerate aging. Multidomain lifestyle interventions have shown promise to slow the accumulation of age-related diseases, a hallmark of aging. However, they have not been assessed among at-risk individuals with these two conditions. We examined the relative impact of 8 years of a multidomain lifestyle intervention on an index of multimorbidity. Design Randomized controlled clinical trial comparing an intensive lifestyle intervention (ILI) that targeted weight loss through caloric restriction and increased physical activity with a control condition of diabetes support and education (DSE). Setting Sixteen U.S. academic centers. Participants A total of 5,145 volunteers, aged 45 to 76, with established type 2 diabetes mellitus and overweight or obesity who met eligibility criteria for a randomized controlled clinical trial. Measurements A multimorbidity index that included nine age-related chronic diseases and death was tracked over 8 years of intervention delivery. Results Among individuals assigned to DSE, the multimorbidity index scores increased by an average of .98 (95% confidence interval [CI] = .94-1.02) over 8 years, compared with .89 (95% CI = .85-.93) among those in the multidomain ILI, which was a 9% difference (P = .003). Relative intervention effects were similar among individuals grouped by baseline body mass index, age, and sex, and they were greater for those with lower levels of multimorbidity index scores at baseline. Conclusions Increases in multimorbidity over time among adults with overweight or obesity and type 2 diabetes mellitus may be slowed by multidomain ILI. J Am Geriatr Soc 68:2249-2256, 2020.

Background Type 2 diabetes and obesity increase the accumulation of health deficits and may accelerate biological aging. Multidomain lifestyle interventions may mitigate against this. Methods Within a large, randomized clinical trial of intensive lifestyle intervention including caloric restriction, increased physical activity, dietary counseling, and risk factor monitoring compared with diabetes support and education, we examined the accumulation of health deficits across 8 years. We used two complementary frailty indices (FIs) based on deficit accumulation, one modeled on work in the Systolic Blood Pressure Intervention Trial and the other including additional deficits related to obesity and type 2 diabetes mellitus. Differences between intervention groups and their consistency among subgroups were assessed with re-randomization tests. Results Data from 4,859 adults (45–76 years at baseline, 59% female) were analyzed. Random assignment to intensive lifestyle intervention was associated with lower FI scores throughout follow-up as captured by areas under curves traced by longitudinal means (p ≤ .001), over which time mean (SE) differences between intervention groups averaged 5.8% (0.9%) and 5.4% (0.9%) for the two indices. At year 8, the percentage of participants classified as frail (FI > 0.21) was lower among intensive lifestyle intervention (39.8% and 54.5%) compared with diabetes support and education (42.7% and 60.9%) for both FIs (both p < .001). Intervention benefits were relatively greater for participants who were older, not obese, and without history of cardiovascular disease at baseline. Conclusions Eight years of multidomain lifestyle intervention create a buffer against the accumulation of age-related health deficits in overweight or obese adults with type 2 diabetes. ClinicalTrials.gov Identifier: NCT00017953

Background: Type 2 diabetes and obesity increase accumulation of health deficits over time and may accelerate biological aging. It is unknown whether multidomain lifestyle interventions can mitigate against this. Methods: Within a large, randomized controlled clinical trial of intensive lifestyle intervention (ILI) including caloric restriction, increased physical activity, dietary counseling, and risk factor monitoring compared with diabetes support and education (DSE) we examined the trajectory of frailty across 8 years. We used two complementary frailty index (FI) definitions, one modeled on work in the Systolic Blood Pressure Intervention Trial; the other including additional deficits related to aging with obesity and type 2 diabetes mellitus. Differences between intervention groups and the consistency of these across clinical subgroups were assessed with re-randomization tests. Results: Data from 4859 adults (45-76 years at baseline, 59% female) were analyzed. Random assignment to ILI was associated with lower FI scores throughout 8 years of follow-up (p0.21) were lower among ILI (39.8% and 54.5%) compared with DSE (42.7% and 60.9%) for the two indices (both p