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Background Multimorbidity is highly prevalent and associated with several adverse health outcomes, including functional limitations. While maintaining physical functioning is relevant for all adults, identifying those with multimorbidity at risk for faster rates of physical functioning decline may help to target interventions to delay the onset and progression of disability. We quantified the association of multimorbidity with rates of long-term disability and objective physical functioning decline. Methods In the Health and Retirement Study, we computed the Multimorbidity-Weighted Index (MWI) by assigning previously validated weights (based on physical functioning) to each chronic condition. We used an adjusted negative binomial regression to assess the association of MWI with disability (measured by basic and instrumental activities of daily living [ADLs, IADLs]) over 16 years, and linear mixed effects models to assess the association of MWI with gait speed and grip strength over 8 years. Results Among 16,616 participants (mean age 67.3, SD 9.7 years; 57.8% women), each additional MWI point was associated with a 10% increase in incidence rate of disability (IRR: 1.10; 95%CI: 1.09, 1.10). In 2,748 participants with data on gait speed and grip strength, each additional MWI point was associated with a decline in gait speed of 0.004 m/s (95%CI: -0.006, -0.001). The association with grip strength was not statistically significant (-0.01 kg, 95%CI: -0.73, 0.04). The rate of decline increased with time for all outcomes, with a significant interaction between time and MWI for disability progression only. Conclusion Multimorbidity, as weighted on physical functioning, was associated with long-term disability, including faster rates of disability progression, and decline in gait speed. Given the importance of maintaining physical functioning and preserving functional independence, MWI is a readily available tool that can help identify adults to target early on for interventions.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.

Objective: Pain, fatigue, and depression commonly co-occur as a symptom cluster in pathological inflammatory states. Psychosocial stressors such as loneliness may lead to similar states through shared mechanisms. We investigated the association of loneliness with pain, fatigue, and depression in older adults. Methods: Using Health and Retirement Study data (N = 11,766), we measured cross-sectional prevalence of frequent, moderate to severe pain; severe fatigue; depressive symptoms; and co-occurrence of symptoms surpassing threshold levels (i.e., symptom cluster). Logistic regression models evaluated associations with loneliness. Results: Pain, fatigue, and depression were reported in 19.2%, 20.0%, and 15.3% of the total sample, respectively. The symptom cluster was seen in 4.9% overall; prevalence in lonely individuals was significantly increased (11.6% vs. 2.3%, p < .0001). After adjusting for demographic variables, loneliness associated with the symptom cluster (adjusted OR = 3.39, 95% CI = 2.91, 3.95) and each symptom (pain adjusted OR = 1.61, 95% CI = 1.48, 1.76; fatigue adjusted OR = 2.02, 95% CI = 1.85, 2.20; depression adjusted OR = 4.34, 95% CI = 3.93, 4.79). Discussion: Loneliness strongly associates with the symptom cluster of pain, fatigue, and depression. Further research should examine causal relationships and investigate whether interventions targeting loneliness mitigate pain, fatigue, and depression.

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the “non‐feminizing” estrogen, 17‐α‐estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log‐rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang–Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex‐specific aspects of aging. Interventions that increase lifespan when started late in life are most likely to be useful in the clinic. Testing genetically diverse mice, the “non‐feminizing” estrogen, 17‐α‐estradiol, extended median male lifespan by 19% (p < 0.0001, log‐rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. Nicotinamide riboside and three other drugs did not affect lifespan in either sex.

Objective The aim was to evaluate prevalence and factors associated with anti-tumor necrosis factor (anti-TNF) de-escalation in older adults with rheumatoid arthritis (RA). Methods We identified adults ≥ 66 years of age with RA on anti-TNF therapy within 6 months after RA diagnosis with at least 6–7 months duration of use (proxy for stable use), using 20% Medicare data from 2008–2017. Patient demographic and clinical characteristics, including concomitant use of glucocorticoid (GC), were collected. Anti-TNF use was categorized as either de-escalation (identified by dosing interval increase, dose reduction, or cessation of use) or continuation. We used (1) an observational cohort design with Cox regression to assess patient characteristics associated with de-escalation and (2) a case–control design with propensity score-adjusted logistic regression to assess the association of de-escalation with different clinical conditions and concomitant medication use. Results We identified 5106 Medicare beneficiaries with RA on anti-TNF, 65.5% of whom had de-escalation. De-escalation was more likely with older age (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.01–1.02) or greater comorbidity (HR 1.07, 95% CI 1.05–1.09), but was less likely with low-income subsidy status (HR 0.85, 95% CI 0.78–0.92), adjusting for patient sex and race/ethnicity. Lower odds of de-escalation were associated with serious infection (odds ratio [OR] 0.79, 95% CI 0.66–0.94), new heart failure diagnosis (OR 0.70, 95% CI 0.52–0.95), and long-term GC use (OR 0.84, 95% CI 0.74–0.95), whereas higher odds were associated with concomitant methotrexate use (OR 1.16, 95% CI 1.03–1.31). Conclusions Anti-TNFs are de-escalated in two-thirds of older adults with RA in usual care. Further study is needed on RA outcomes after anti-TNF de-escalation.

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% ( p  = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% ( p  = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE ( n ) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang–Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.

Abstract Pain, fatigue, and depression form a well-recognized symptom cluster that is posited to have a shared mechanism. It is possible that chronic psychosocial stressors such as loneliness may impact the central nervous system and immune system, potentially leading to symptom cluster development. Loneliness is an increasingly recognized type of psychosocial stress, especially among older American adults. Thus, we investigated whether loneliness increased risk of developing the symptom cluster of pain, fatigue, and depression over time. Using Health and Retirement Study data from 2006 - 2016, we examined self-respondents ≥50 years-old for the presence of co-occurring pain, fatigue, and depressive symptoms surpassing threshold levels (ie., the symptom cluster). Loneliness (measured by the 3-item UCLA Loneliness Scale) at baseline was used as the predictor of interest. Of the total sample (n=11,766), n=5,956 (50.6%) had up to two complete sets of follow-up symptom cluster measurements. Logistic regression models for longitudinal data were fitted using a generalized estimating equation (GEE). After adjusting for demographic and clinical variables, loneliness strongly predicted the development of the symptom cluster (adjusted OR=3.16 (95% CI 2.77, 3.61)) as well as each component symptom (pain adjusted OR=1.54 (95% CI 1.42, 1.67); fatigue adjusted OR=1.88 (95% CI 1.74, 2.03); depression adjusted OR = 3.87 (95% CI 3.55, 4.21). Further research should investigate whether interventions targeting loneliness or other psychosocial stressors may have a role in prevention of this symptom cluster.

Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase ( p  = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p  = 0.004) in males and a significant decline (6%, p  = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p  = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

There are few data on mid-life sensory health and its contribution to health and disability outcomes. The Study of Women’s Health Across the Nation—Michigan site (N=252 women, mean age=66.0 years) collected comprehensive data regarding ocular health to estimate the burden and correlates of vision impairment (VI) and unmet need for vision correction in this population. The prevalence of VI based on presenting and best-corrected visual acuity was 11.1% (95% CI 7.5,15.7) and 2.8% (95% CI 1.1,5.6), respectively. Thus, 75.0% of presenting VI was correctable, yet only 29.0% of women wore an appropriate eyeglass prescription. Black women and those with greater financial strain or less education were more likely to have presenting VI, but there were no differences in best-corrected VI. This presentation will include a discussion of the contributions of SWAN to the study of sensory aging, as well as methodological considerations for research from a mid-life aging cohort. Part of a symposium sponsored by Sensory Health Interest Group.