Background: Sex differences underlie the onset and severity of many diseases, and sex hormones likely interact with genetics in phenotypes such as peripheral neuropathy (PN). We previously ...demonstrated that female mice are protected from diabetic and age-related PN until reproductive senescence at middle age, yet PN was not mitigated with rapamycin longevity treatment. 17α-Estradiol (17α-E2) is an alternative, validated longevity treatment and is non-feminizing. Methods: We used genetically diverse HET3 mice to examine impacts of 17α-E2 on metabolic/adipose functions and peripheral nerve health across aging, as HET3 is a reproducible mix of 4 inbred strains that allows for phenotype data to be statistically compared to an individual animal's genetics. Middle aged (~51 wks) and older (~84 weeks) male HET3 mice received 17α-E2 treatment in diet for 17 weeks. Results: We observed increased grip and contractility torque, as well as improved neuromuscular junction function, in middle aged 17α-E2 treated mice. However, 17α-E2 treatment improved intraepidermal innervation (a measure of PN) only in older mice. Reduced fat mass was seen in all 17α-E2-treated mice regardless of age, with improved glucose sensitivity evident only in older male mice. Increased energy expenditure was seen in 17α-E2 treated middle aged mice. Interestingly, these metabolic and neural endpoint data varied by genetic strain. For example, grip strength improvement was most evident when C57BL/6 or DBA/2 strain contribution was low. In addition to treatment with sex hormones, we have separately developed a novel method for delivering adipocytetropic adeno-associated virus (AAV) to overexpress neurotrophic factors as a gene therapy approach to mitigate PN in skin and subdermal tissues, using a patent-pending theragnostic device we have designed. Conclusions: Taken together, 17α-E2 treatment and/or intra-adipose gene therapies are translationally relevant ways to maintain metabolic and nerve function with aging.
Background: Lifetime number of pregnancies (LTP) and age at first pregnancy (AFP) may contribute to women's long-term weight gain, but current evidence is limited to cross-sectional studies with ...single time-point assessments of weight and adiposity. Here, we investigated associations of LTP and AFP with weight, waist circumference (WC), and body fat (BF) assessed longitudinally from mid-adulthood to midlife. Methods: Among 1054 women enrolled during a pregnancy in the Project Viva cohort, participants reported AFP at the 18-y follow-up study visit. If this information was missing and women were nulliparous at study enrollment, we considered the age at delivery of the index pregnancy as AFP (<23, 23-29, 30-34 ref, 35-39, >40 y). LTP were reported at the 18-y visit (1, 2 ref, 3, >4). Outcomes were repeated measures of postpartum weight (6 mo, 3, 7, 12, 18 y), WC (3, 7, 12, 18 y), and BF (kg and %, 7, 12, 18 y). We used linear mixedeffects models adjusted for age at outcome assessment, race/ethnicity, education, household income, pre-pregnancy body mass index, and AFP (only models for LTP). Results: Mean age at enrollment was 32.3 y (SD 4.7); 46% had their first pregnancy at 30-34 y, and 50% had 2 pregnancies. Younger AFP was associated with higher average weight through follow-up. For example, compared to AFP 30-34 y, women aged <23 y AFP had 2.6 (95% CI: 0.3, 4.9) kg higher weight across 18 y postpartum. Similarly, those 23-29 y AFP had 1.9 (0.6, 3.2) kg higher weight than the reference across the same timeframe. Results were similar for WC and BF. We observed a J-shaped association between LTP and adiposity. Women with >4 pregnancies (vs. 2) had 4.9 (1.2, 8.7) kg higher weight, 5.2 (1.7, 8.7) cm higher WC, and 4.4 kg and 3.2% higher BF across follow-up. Women with 1 pregnancy (vs. 2) had higher BF (3.0 kg and 1.9%). Conclusions: Earlier age at first pregnancy and having had 1 or >4 pregnancies are associated with higher adiposity across midlife.
Background: Advancing age is associated with a progressive impairment in glucose tolerance and increased risk of type 2 diabetes. Exogenous ketone ester (KE) supplementation prior to meals improves ...glucose tolerance in both young healthy-weight individuals and those with obesity. However, whether short-term exogenous KE supplementation improves glucose tolerance in overnight fasted healthy middle-aged and older individuals is not known. Methods: Utilizing a randomized double-blind and placebo-controlled crossover design, 11 adults (age = 59 ± 6.7 years, body mass index = 27.3 ± 4.4 kg/m2) consumed KE 25gr 3×/day (ΔG, HVMN Inc.) and placebo for 2 weeks. A 2-week washout period separated the treatments. Glucose tolerance and 24-h glucose control were assessed via an oral glucose tolerance test (OGTT) after an overnight fast (no premeal KE) and a continuous glucose monitor (CGM), respectively. Results: KE supplementation significantly increased urinary β-hydroxybutyrate levels to 0.55 ± 0.03 mM (p < 0.05) to reach nutritional ketosis. Compared with placebo, KE supplementation did not significantly alter fasting glucose (Baselineplacebo = 5 ± 0.4; Postplacebo = 5.3 ± 0.4 mmol/L, vs BaselineKE = 5.2 ± 0.4; PostKE = 5.3 ± 0.5 mmol/L), fasting insulin (Baselineplacebo = 15.1 ± 6.2; Postplacebo = 16.7 ± 4.7 uIU/mL, vs BaselineKE = 16.4 ± 9.4; PostKE = 20.4 ± 15.3 uIU/mL), or OGTT incremental area under the curve (Baselineplacebo = 324 ± 196.1; Postplacebo = 252 ± 162.2 au, vs BaselineKE = 278 ± 164.6; PostKE = 293 ± 192.8 au). In addition, 24-h Mean Blood Glucose (Baselinep|acebo = 4.99 ± 0.62; Postp|acebo = 4.82 ± 0.55 mmol/L, vs BaselineKE = 4.94 ± 0.43; PostKE = 4.88 ± 0.67 mmol/L) did not change with the interventions. Conclusions: Exogenous 2-week KE supplementation did not influence glycemic control in middle-aged and older adults. Future studies are needed to explore acute vs chronic effect of exogenous KE on glucose homeostasis.
The midlife crisis has become a cliché in modern society. Since the mid-twentieth century, the term has been used to explain infidelity in middle-aged men, disillusionment with personal achievements, ...the pain and sadness associated with separation and divorce, and the fear of approaching death. This book provides a meticulously researched account of the social and cultural conditions in which middle-aged men and women began to reevaluate their hopes and dreams, reassess their relationships, and seek new forms of identity and fresh pathways to self-satisfaction. Drawing on a rich seam of literary, medical, media, and cinematic sources, as well as personal accounts, Broken Dreams explores how the crises of middle-aged men and women were shaped by increased life expectancy, changing family structures, shifting patterns of work, and the rise of individualism.
Abstract
Introduction
Functional limitations become increasingly common and debilitating as individuals age, potentially impacting several facets of well-being. As such, it is important to understand ...malleable factors that may potentially impact functional limitation outcomes. Both sleep and perceived control have been linked to the development of functional limitation. The current study sought to clarify the unique contributions of both sleep quality and perceived control to functional limitation status in middle-aged and older adults.
Methods
Data from the second wave of the Midlife in the United States study were used for the current study. Participants included 527 participants (59.9% female, Mage=59.83 years, SD=9.75 years) who completed measures of functional limitation levels (Functional Status Questionnaire), subjective sleep quality (Pittsburg Sleep Quality Index), and perceived control (MIDI Sense of Control Scales). A hierarchical regression analysis was conducted to examine sleep quality and perceived control as predictors in a unique model for predicting functional limitation. Demographic variables of age, gender, and race were used as covariates in study analyses.
Results
The overall model predicted 19.0% of the variance in functional limitation levels. Sleep quality was significantly associated with self-reported functional limitation (β=-.27, p<.001) over and above perceived control (β=.20, p<.001). Specifically, findings indicate that worse sleep quality is associated with increased functional limitation, while higher levels of perceived control are associated with lower levels of functional limitation.
Conclusion
Though perceived control is known to be associated with functional limitation status, the present study suggests a unique effect of sleep quality on functional limitation even after accounting for perceived control. Due to the potential for negative effects of functional limitation in middle-aged to older adults, it is important to identify and target constructs for research and intervention related to the development of these limitations. Care models for individuals who report experiencing functional limitations may benefit from targeting sleep health and control beliefs in intervention and assessment.
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