Protective Effects of Familial Longevity Decrease with Age and Become Negligible for Centenarians

It is known that biological relatives of long-lived individuals demonstrate lower mortality and longer lifespan compared to relatives of shorter-lived individuals, and at least part of this advantage is likely to be genetic. Less information, however, is available about effects of familial longevity on age-specific mortality trajectories. We compared mortality patterns after age 50 years for 10,045 siblings of U.S. centenarians and 12,308 siblings of shorter-lived individuals (died at age 65 years). Similar comparisons were made for sons and daughters of longer-lived parents (both parents lived 80 years and more) and shorter-lived parents (both parents lived less than 80 years) within each group of siblings. Although relatives of longer-lived individuals have lower mortality at younger ages compared to relatives of shorter lived individuals, this mortality advantage practically disappears by age 100 years. To validate this observation further, we analyzed survival of 3,408 U.S. centenarians born in 1890-97 with known information on maternal and paternal lifespan. We found using the Cox proportional hazards model that both maternal and paternal longevity (lifespan 80+ years) is not significantly associated with survival after age 100 years. The results are compatible with the predictions of reliability theory of aging suggesting higher initial levels of system redundancy (reserves) in individuals with protective familial/genetic background and hence lower initial mortality. Heterogeneity hypothesis is another possible explanation for the observed phenomena.

Physical Robustness and Resilience Among Long-Lived Female Siblings: A Comparison With Sporadic Long-Livers

Background: Long-lived individuals are central in studies of determinants of healthy longevity. However, few pro-longevity factors have been identified, presumably because of “phenocopies”, i.e. individuals that live long by chance. Familial longevity cases may include less phenocopies than sporadic cases and provide better insights into longevity mechanisms. Here we examined whether long-lived female siblings have a better ability to avoid common diseases at ages 65+ (proxy for “robustness”) and/or survive to extreme ages (proxy for “resilience”) compared to sporadic long-livers. Methods: 1,156 long-lived female siblings were selected from three nationwide Danish studies (DOS, GeHA, LLFS) and age-matched with sporadic long-lived female control from the Danish population. Outcomes included cumulative incidence of common health disorders from age 65, and overall survival from 2006 onwards. Logistic and Cox models were used to evaluate incidence and survival respectively. Results: Long-lived female siblings had significantly lower risks of hypertensive (OR=0.84; 95%CI=0.71-0.99) and cerebrovascular (OR=0.73; 95%CI=0.55-0.96) diseases and depression (OR=0.74; 95%CI=0.62-0.88) at ages 65+, and better survival to extreme ages (HR=0.71; 95%CI= 0.63-0.81) compared to sporadic long-livers. After adjusting for diseases above, the association with mortality changed only marginally (HR=0.73 (0.64-0.83)). Conclusion: Familial longevity cases could be more informative for studying mechanisms of healthy longevity than sporadic cases. Long-lived female siblings demonstrate better physical robustness and resilience than their age-peers from general population, which might be attributed to a genetic component in familial longevity.

The Long Life Family Study: Sequencing Exceptional Pedigrees for Rare Protective Variants

The Long Life Family Study (LLFS) has longitudinally measured key aging phenotypes on 4,953 participants (539 pedigrees) in the USA and Denmark selected for exceptional familial longevity. On average, both generations of the LLFS sample are healthier than average for their age/sex, for many phenotypes. However, the pedigrees are heterogeneous, with different families showing familial clustering of protection for different phenotypes. Linkage analyses identified extremely strong genetic linkage peaks for many cross-sectional as well as longitudinal trajectory rates of change phenotypes. These peaks are NOT explained by GWAS SNPs (either measured or imputed). Pedigree specific HLODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. Whole Genome Sequencing, a third longitudinal visit, and extensive OMICs (transcriptomics, epigenomics, metabolomics and proteomics) will help us resolve the mechanisms behind these protective genetically linked variants, and could illuminate new biology and enable new therapeutics.

Pathway Analysis of Leisure Activity and Cognitive Function in the Long Life Family Study

Familial longevity and greater involvement in activities purported to build cognitive reserve (e.g. education, cognitively stimulating leisure activity) have both been associated with better cognitive function in later life, yet little is known about how these protective factors relate with one another. In this work, we modeled the associations among familial longevity, proxies of cognitive reserve, and cognitive function in the Long Life Family Study (LLFS). We assessed cognitive function using a comprehensive battery of neuropsychological tests (i.e. Digit-Spans, California Verbal Learning Test, Rey-Osterrieth Complex Figure, phonemic fluency, category fluency, Word Generation, DKEFS Sorting Test, and logical memory) in a subset of LLFS family members and a referent cohort (N=314, mean age 75.7±14.6 years). To model these associations, we used a series of Bayesian hierarchical regression pathways that incorporate a random effect for family relatedness, adjusted by age and sex. All continuous variables were rescaled and bounded to be approximately between (0,1) in order to standardize regression coefficients and to allow for an asymmetrical beta-distribution. Controlling for education level, age, and sex, referents had greater engagement in late-life cognitive activities compared to LLFS family members, β=0.38 (95% CI: 0.18 to 0.57). In turn, those with higher markers of cognitive reserve exhibited better neuropsychological performance. Despite LLFS family members having lower participation in cognitively stimulating leisure activities, there were no differences between LLFS family members and referents on cognitive test performance. These results suggest long-lived family members may have more unique pathways (i.e. genetic/environmental) that preserve cognition later in life.

Early Differences in Cognition Associated With Familial Longevity and ApoE Genotype Using Digital Technology

Merging digital technologies with neuropsychological testing allows for collection of novel metrics that may reveal early, subtle differences in cognitive functioning. We examined whether digital pen metrics from the Clock Drawing Test (CDT) differentiate healthy agers (i.e., individuals with familial longevity) from spouses and individuals by APOE genotype. We used generalized estimating equations adjusted for sociodemographics, familial longevity, and APOE genotype. Among 1974 participants with correct clocks (mean age 71±10 years), familial longevity was associated with better cognitive processing (i.e., shorter latencies/thinking time before cognitively demanding components) whereas the e4 allele was associated with smaller clock diameter and longer latencies. The e2 allele was negatively associated with total time and latencies. Therefore, digital metrics captured differences in cognitive processing among individuals with correct clocks and thus may be more sensitive than traditional scores. Additionally, familial longevity may confer cognitive advantages that are distinct from the risk/protection afforded by APOE genotype.

Circulating Thyroid Hormone Profile in Response to a Triiodothyronine Challenge in Familial Longevity

Context Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown. Objective We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls. Methods In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 µg 3,5,3′-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration. Results Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events. T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P = .11, fT3 GLM P = .46). TSH levels decreased in a biphasic manner and started returning to baseline by day 5. The TSH concentration profile over 5 days was similar between offspring and controls (GLM P = .08), as was the relative TSH decline (%). Conclusions Members of long-lived families have neither higher T3 turnover nor diminished negative feedback of T3 on TSH secretion. The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated.

Familial Longevity is Associated with an Attenuated Thyroidal Response to Recombinant Human Thyroid Stimulating Hormone

Context Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown. Objective We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels. Methods We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations. Results The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUC TSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07). Conclusions The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners.

A COMPARATIVE ANALYSIS ON HEALTHY LONGEVITY PHENOTYPES BETWEEN CHINESE AND ITALIAN CENTENARIANS

This paper reviews and compares demographic, socioeconomic, behavioral (including diet) characteristics and heath phenotypes of centenarians in China and Italy. The results revealed that the interactions between familial longevity and any one of the three environmental factors (receipt of adequate medical care when ill as a child, number of living children, and household economic conditions) were significantly associated with the three health outcome indicators (IADL, self-rated life satisfaction, and anxiety-loneness) at old ages. We discovered that the effects of these environmental factors on the health outcome indicators were substantially stronger among elders who had no family history of longevity compared to centenarians’ children who likely carry genes and/or inherited healthy behavior and better lifestyle from long-lived parents.