Mark A. Espeland

Background: Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. Methods: We examined 5844 women from the Women’s Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as (1) survival to age 90 with preserved cognition (n = 1726, 29.5%) or (2) survival to age 90 with cognitive impairment (n = 956, 16.4%); vs (3) death before age 90 (n = 2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs death before age 90), also adjusting for covariates. Results: Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (odds ratio [OR] = 0.66; 95% CI 0.61-0.71), PCGrimAge (OR = 0.64; 95% CI 0.59-0.69), PCPhenoAge (OR = 0.73; 95% CI 0.68-0.78), and DunedinPACE (OR = 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. Conclusions: All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Background: The relationship between the duration of napping and cognitive function is unclear. We examine this association by analyzing baseline data from the US POINTER-zzz Sleep Ancillary Study. Methods: This study evaluates sleep assessments obtained via home apnea-screening device, wrist actigraphy, and sleep diaries among 686 older adult participants. Naps were defined as sleep periods with at least 30 continuous minutes outside of the primary period of sleep or the longest sleep duration. We conducted linear regression analyses to test the association between napping minutes and baseline global cognitive function and its domains, including executive function, episodic memory, and processing speed. We also examined whether the association between duration of napping and cognitive function outcomes differed by the presence (n = 223) or absence of sleep apnea (n = 463). Results: For the total sample, greater minutes of napping were associated with decreased processing speed [β = −0.0973 (95% CI = −0.1664, −0.0282)]. The interaction analyses between sleep apnea and napping did not reach statistical significance, providing no evidence that sleep apnea modifies the association between napping and cognition in the total sample. Greater minutes of napping were associated with poor executive function in participants with sleep apnea and who were in an under-represented ethno-racial group [β = −0.2493 (95% CI = −0.4943, −0.0042)]. Conclusions: Study findings are exploratory and suggest that it may be important to detect and treat sleep apnea for possible cognitive benefits, especially in certain subgroups of older adults. Clinical trial registration number: NCT03688126; https://clinicaltrials.gov/ct2/show/NCT03688126.

INTRODUCTION: Multidomain lifestyle interventions have been demonstrated to benefit cognitive function but it is unknown whether they reduce risk for clinically significant cognitive impairment sCI (mild cognitive impairment or dementia). METHODS: The Action for Health in Diabetes administered repeated cognitive assessments in adults who had been enrolled in a 10‐year clinical trial of a multidomain Intensive Lifestyle Intervention (ILI) versus Diabetes Support and Education (DSE). RESULTS: N = 3655 underwent at least one assessment of cognitive status during 12–14 years of post‐trial follow‐up. The relative impact of ILI on sCI incidence varied by baseline body mass index (BMI, interaction p = 0.004): hazard ratio (HR) = 0.64 [0.46,0.89] for BMI 25–29 kg/m ² , HR = 0.98 [0.85,1.16] for BMI 30–39 kg/m ² , and HR = 1.40 [1.01,1.93] for BMI ≥ 40 kg/m ² . DISCUSSION: A long‐term multidomain lifestyle intervention may markedly reduce the risk of incident sCI among adults with type 2 diabetes and overweight but not obesity.

Background: Evidence suggests that dysregulation of the renin angiotensin system (RAS) is associated with the pathophysiologic process of Alzheimer's disease (AD). Few studies have evaluated the relationship between circulating RAS components and incident cognitive decline or impairment. Objective: Our study aims to evaluate the relationship between circulating RAS biomarkers (angiotensin II [ANGII], angiotensin 1-7 [ANG1-7], angiotensin converting enzyme-1 [ACE-1], and 2 [ACE-2]), in initially cognitively healthy adults, and incident cognitive decline and cognitive impairment. Methods: In this secondary analysis, 310 community-dwelling participants from the randomized controlled Action for Health in Diabetes (Look AHEAD) study without dementia, who were not on RAS-altering medication, were included. Results: Participants, compared to those excluded, were more likely to be female (65%), white (76%), overweight (34%), have lower baseline HbA1c (6.7%), lower SBP (119.7 mmHg), lower serum creatinine (0.79 mg/dL), higher total cholesterol (190.1 mg/dL) and LDL (112.5 mg/dL), and higher history of dyslipidemia (65%) at baseline. 1 SD increase of ANG1-7 measured in year 1 was associated with lower odds of cognitive impairment (OR = 0.35, 95% CI 0.16-0.77; p = 0.001), while higher ANG1-7 levels predicted better global cognitive function [β x 10 ⁻³ = 1.03 (0.50); p = 0.039], 15 years later. Conclusions: These results provide preliminary evidence that circulating RAS components are predictive of protection against cognitive impairment and decline and may serve as a marker of the early stages of dementia. Further research is warranted to fully understand the relationship between the brain and the circulatory RAS.

Aims: To identify frailty subtypes among African American adults with and without diabetes. Methods: This analysis included data from 3979 African American men and women who enrolled in the Jackson Heart Study at baseline (Exam1: 2000–2004). To identify frailty subtypes, we selected 25 age‐related deficits in health and functional outcomes as indicator variables to use in multiple‐group latent class analysis (LCA), with diabetes status as the grouping variable. Components included markers of general health, physical function, social engagement, work, activities of daily living, behaviour/lifestyle, sleep, age‐related chronic diseases, pain, clinical biomarkers, and sensorineural abilities. Results: Three frailty groups were identified for adults with and without diabetes: the ‘severely frail’ group (15.2% of those without diabetes; 22.4% of those with diabetes); the ‘moderately frail’ group (21.7% of those without diabetes; 13.1% of those with diabetes); and the ‘not frail’ group (63.1% of those without diabetes; 64.5% of those with diabetes). Adults in the ‘severely frail’ group had higher probabilities of poor health perception, limited mobility, high blood pressure, obesity, and claudication, and this was similar for those with and without diabetes. Among individuals in the ‘moderately frail’ group, higher probabilities of poor health perception, limited mobility, high blood pressure, obesity, and claudication were found among those with diabetes, whereas only sleep quality and obesity had higher probabilities among those without diabetes. Conclusions: Three heterogeneous frailty subgroups were identified among African American adults, with similarities and differences noted for those with and without diabetes with regard to high probabilities for certain deficits in health and functional outcomes. Further investigation is needed to evaluate if these subgroups predict health‐related outcomes.

Background: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear. Methods: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability than the Self-Guided intervention. A modified FI (mFI) was developed from data collected at baseline, 12, and 24 months. Results: The trial enrolled 2111 adults (ages 60-79 years) who were at increased risk for accelerated cognitive decline. At 24 months, the mean (standard error) changes from baseline of a 31-component mFI were −0.009 (0.002) for Self-Guided and −0.024 (0.002) for Structured participants, a difference averaging −0.014 [−0.019, −0.008] (P < .0001). Group differences were similar across subgroups based on age, sex, body mass index, diabetes, and baseline mFI. Changes in mFI did not account for the relative cognitive benefits provided by the Structured intervention compared to the Self-Guided intervention. Conclusions: Multidomain lifestyle interventions may decrease frailty and slow aging processes with greater structure and intensity, resulting in greater benefits. Clinical Trial Registration Number: NCT03688126

In animal models, caloric restriction (CR) and time-restricted eating (TRE) extend lifespan and healthspan; however, the long-term benefits in humans are unknown. The goal of the Health, Aging and Later-Life Outcomes Pilot (HALLO-P) was to inform the design of a definitive trial to evaluate the long-term effects of CR and TRE in older adults with overweight or obesity. HALLO-P randomized 90 older (≥60 yrs) adults with obesity or overweight to one of three 9-month interventions: 1) 20% CR delivered in-person; 2) 20% CR delivered remotely (RCR); and 3) 8-hr TRE with ad libitum caloric intake. The degree of sustained CR (by doubly labeled water), the sustainability of TRE, participant retention, and changes in body mass and composition, physical performance and cardiometabolic risk factors were examined. Participants had a mean (SD) age of 67.2 (4.9) yrs and BMI of 31.7 (2.9) kg/m²; 62% were female and 83% White. Participant retention was 92%. The mean (SD) percent CR was 4.5% (11.0) in CR and 6.0% (10.3) in RCR. TRE participants reported eating within an 8.5-hr window a median of 84% of days. Mean change in body mass was -4.4, -6.7 and -1.0 kg in CR, RCR and TRE, respectively. CR and RCR lost fat and lean soft tissue. Chair stand and 400-m walk times improved in RCR and TRE and there were improvements in glucose and cholesterol levels in all three groups. HALLO-P showed that the CR and TRE interventions were feasible and associated with improvements in health status over 9 months despite not achieving the target CR.

Objective: We explore associations that four weight-sensitive and neuroactive cytokines – adiponectin, leptin, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) – have with cross-sectional brain volumes among adults with obesity or overweight and with type 2 diabetes (T2D). Methods: Cytokine concentrations were assayed at baseline and proximal to the end of two 10-year lifestyle interventions among 233 Look AHEAD trial participants. Magnetic resonance imaging measured total, white, and gray matter brain volumes. Associations that cytokine concentrations and changes in concentrations had with brain volumes and weight changes were assessed. Results: Higher IL-6 and VEGF concentrations were associated with smaller total brain volumes (β=-3.00 [95% CI -14.82,-3.07] and β=-2.79 [-10.08,-1.74] log-units/cc respectively). Higher leptin concentrations were associated with higher white matter volumes (β=2.00 [-0.06,6.92] log-units/cc). Increases in adiponectin were associated with greater total brain volumes (β=2.14 [0.50,11.94] log-units/cc). Higher leptin and IL-6 concentrations were associated cross-sectionally with greater body mass index (BMI) and increases in leptin, IL-6, and VEGF concentrations were associated with increases in BMI. Neither lifestyle intervention nor changes in BMI materially affected associations between cytokines and brain volumes. Conclusions: Weight-sensitive neuroactive cytokine concentrations are related to brain volumes. Weight changes and lifestyle interventions targeting weight loss may not materially influence these associations in adults with T2D.

The 10-year Action for Health in Diabetes (Look AHEAD) clinical trial compared a multidomain intensive lifestyle intervention to a diabetes support and education program with respect to major cardiovascular disease events (primary outcome) and other diabetes- and obesity-related outcomes. Follow-up of the cohort continues to add other aging-related outcomes and conditions to identify the long-term consequences of factors related to lifestyle and medical care. In this transition to a study of aging among individuals at risk for accelerated aging due to type 2 diabetes and overweight or obesity, the investigators have retrospectively reframed the study using the perspective of geroscience. This perspective strengthens the importance of lifestyle changes as a core component for medical care for these individuals to slow biological aging.