Unbiased Proteomics and Targeted Biomarkers Associated With Exceptional Longevity and Multimorbidity in Humans

Biomarkers ideal for geroscience trials could be those simultaneously identified using targeted and discovery assays and which strongly associate with complementary disease (multimorbidity) and longevity (exceptional survival) outcomes. To identify a tractable set of biomarkers for use in geroscience trials, we used the Cardiovascular Health Study (CHS), whose participant makeup closely aligns with the Targeting Aging with MEtformin (TAME) trial. In ~4800 CHS participants, quantitative assays of nine a priori-identified biomarkers were used to construct a biomarker index which strongly associated with the TAME primary outcome of mortality and multimorbidity over 6 and 10 years of follow-up. In ~3000 CHS participants, 1300 proteins were measured with unbiased aptamer proteomics and associated with survival to age 90 over 25 years of follow-up. Proteins in the biomarker index were identified as some of the strongest associated with survival to 90. This convergent evidence suggests these biomarkers may be well-suited for geroscience trials.

A-17 Examining Cognitive Trajectories in SuperAgers within the LonGenity Study

Objective Rogalski and colleagues (2013) use the term SuperAgers to indicate individuals aged 80 and older who have exceptional memory with the goal of clarifying factors that impact successful aging. Using a modified definition, we explored cognitive trajectories of SuperAgers within our longitudinal study of the genetic factors associated with exceptional longevity (OPEL) in individuals of Ashkenazi Jewish descent. Method LonGenity Study participants complete annual physical and cognitive assessments which include the Free and Cued Selective Reminding Test (FCSRT) and WMS-R Logical Memory (LMI). All participants who completed a visit at age 80 were included in the analysis (N = 230; 56.5% female; mean education 17.57 ± 2.74 years; 46.5% OPEL; median follow-up 4 years). Twenty-one participants met modified SuperAger criteria (FCSRT: >38 and LMI: >25; no other cognitive impairment). Descriptive statistics, t-tests, and linear mixed effects models of cognitive trajectories were used to examine the differences between SuperAgers and non-SuperAgers. Results Although there were no differences in demographics or familial history of exceptional longevity, SuperAgers were less likely to have a history of cardiac problems (p = 0.02). Overall cognitive functioning remained stable with age in the SuperAgers, whereas non-SuperAgers demonstrated declining overall cognition with age (β = −0.029, CI: −0.036—0.022). Memory task performances demonstrated a similar discrepancy in trajectories. Conclusion(s) In our unique and high functioning population, SuperAgers as defined at age 80 do not demonstrate the typical cognitive declines thought to be associated with age. Vascular risk factors appear to play a role, but further investigation including exploring genetic markers and MRI is warranted.

New Perspectives on Avian Models for Studies of Basic Aging Processes

Avian models have the potential to elucidate basic cellular and molecular mechanisms underlying the slow aging rates and exceptional longevity typical of this group of vertebrates. To date, most studies of avian aging have focused on relatively few of the phenomena now thought to be intrinsic to the aging process, but primarily on responses to oxidative stress and telomere dynamics. But a variety of whole-animal and cell-based approaches to avian aging and stress resistance have been developed—especially the use of primary cell lines and isolated erythrocytes—which permit other processes to be investigated. In this review, we highlight newer studies using these approaches. We also discuss recent research on age-related changes in neural function in birds in the context of sensory changes relevant to homing and navigation, as well as the maintenance of song. More recently, with the advent of “-omic” methodologies, including whole-genome studies, new approaches have gained momentum for investigating the mechanistic basis of aging in birds. Overall, current research suggests that birds exhibit an enhanced resistance to the detrimental effects of oxidative damage and maintain higher than expected levels of cellular function as they age. There is also evidence that genetic signatures associated with cellular defenses, as well as metabolic and immune function, are enhanced in birds but data are still lacking relative to that available from more conventional model organisms. We are optimistic that continued development of avian models in geroscience, especially under controlled laboratory conditions, will provide novel insights into the exceptional longevity of this animal taxon.

The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men

Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age < 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p < 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p < 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p < 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age < 88 years, and 30% and 11%, among men age ≥ 88 years (p < 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age < 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

How the heat shock axis, repair pathways, and proteostasis impact the rate of aging is not fully understood. Recent reports indicate that normal aging leads to a 50% change in several regulatory elements of the heat shock axis. Most notably is the age-dependent enhancement of inhibitory signals associated with accumulated heat shock proteins and hyper-acetylation associated with marked attenuation of heat shock factor 1 (HSF1)–DNA binding activity. Because exceptional longevity is associated with increased resistance to stress, this study evaluated regulatory check points of the heat shock axis in liver extracts from 12 months and 24 months long-lived Ames dwarf mice and compared these findings with aging wild-type mice. This analysis showed that 12M dwarf and wild-type mice have comparable stress responses, whereas old dwarf mice, unlike old wild-type mice, preserve and enhance activating elements of the heat shock axis. Old dwarf mice thwart negative regulation of the heat shock axis typically observed in usual aging such as noted in HSF1 phosphorylation at Ser307 residue, acetylation within its DNA binding domain, and reduction in proteins that attenuate HSF1–DNA binding. Unlike usual aging, dwarf HSF1 protein and mRNA levels increase with age and further enhance by stress. Together these observations suggest that exceptional longevity is associated with compensatory and enhanced HSF1 regulation as an adaptation to age-dependent forces that otherwise downregulate the heat shock axis.

Reproductive activation in honeybee ( Apis mellifera ) workers protects against abiotic and biotic stress

Social insect reproductives exhibit exceptional longevity instead of the classic trade-off between somatic maintenance and reproduction. Even normally sterile workers experience a significant increase in life expectancy when they assume a reproductive role. The mechanisms that enable the positive relation between the antagonistic demands of reproduction and somatic maintenance are unclear. To isolate the effect of reproductive activation, honeybee workers were induced to activate their ovaries. These reproductively activated workers were compared to controls for survival and gene expression patterns after exposure to Israeli Acute Paralysis Virus or the oxidative stressor paraquat. Reproductive activation increased survival, indicating better immunity and oxidative stress resistance. After qPCR analysis confirmed our experimental treatments at the physiological level, whole transcriptome analysis revealed that paraquat treatment significantly changed the expression of 1277 genes in the control workers but only two genes in reproductively activated workers, indicating that reproductive activation preemptively protects against oxidative stress. Significant overlap between genes that were upregulated by reproductive activation and in response to paraquat included prominent members of signalling pathways and anti-oxidants known to affect ageing. Thus, while our results confirm a central role of vitellogenin, they also point to other mechanisms to explain the molecular basis of the lack of a cost of reproduction and the exceptional longevity of social insect reproductives. Thus, socially induced reproductive activation preemptively protects honeybee workers against stressors, explaining their longevity. This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?'