The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.

Shared genetic aetiology between childhood intelligence and longevity

BackgroundIntelligence and longevity are phenotypically and genetically correlated. Whereas molecular genetic data has been used to show that adult intelligence is genetically correlated with longevity, no such analysis has examined the association between childhood intelligence and longevity.Method and ResultsUsing genome wide association study data on childhood intelligence (n = 12,441) and on parental longevity (n = 389,166) we found a positive genetic correlation of rg = 0.35 (SE = 0.14, P = 0.01) between childhood intelligence and parental longevity.ConclusionThese results add to the weight of evidence that the phenotypic link between childhood intelligence and longevity is, partly, accounted for by shared genetic aetiology.

The effect of Alzheimer’s disease-associated genetic variants on longevity

The genetics underlying human longevity is influenced by the genetic risk to develop -or escape- age-related diseases. As Alzheimer’s disease (AD) represents one of the most common conditions at old age, an interplay between genetic factors for AD and longevity is expected.We explored this interplay by studying the prevalence of 38 AD-associated single-nucleotide-polymorphisms (SNPs) identified in AD-GWAS, in self-reported cognitively healthy centenarians, and we replicated findings in the largest GWAS on parental-longevity.We found that 28/38 SNPs identified to associate with increased AD-risk also associated with decreased odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. When grouping the SNPs based on these distributions, we found three groups: 17 variants increased AD-risk more than they decreased the risk of longevity (AD-group): these variants were functionally enriched for β-amyloid metabolism and immune signaling, and they were enriched in microglia. 11 variants reported a larger effect on longevity as compared to their AD-effect (Longevity-group): these variants were enriched for endocytosis/immune signaling, and at the cell-type level were enriched in microglia and endothelial cells. Next to AD, these variants were previously associated with other aging-related diseases, including cardiovascular and autoimmune diseases, and cancer. Unexpectedly, 10 variants associated with an increased risk of both AD and longevity (Unexpected-group). The effect of the SNPs in AD- and Longevity-groups replicated in the largest GWAS on parental-longevity, while the effects on longevity of the SNPs in the Unexpected-group could not be replicated, suggesting that these effects may not be robust across different studies.Our study shows that some AD-associated variants negatively affect longevity primarily by their increased risk of AD, while other variants negatively affect longevity through an increased risk of multiple age-related diseases, including AD.

Parental Longevity Is Associated With Brain Volumes in Selected Areas

A few studies report that parental longevity is associated with faster gait speed, less memory decline, a lower risk of Alzheimer’s disease, and lower white matter hyperintensities. Data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain volumes. We identified 10,513 participants from UK Biobank (mean age=58±6, ranged40-70, 50%women) with data on parental longevity and information on MRI regional brain volumes that have been related to executive function (dorsolateral prefrontal cortex), memory (hippocampus, parahippocampal gyrus, inferior temporal lobe, middle temporal lobe) and motor function (precentral gyrus, putamen, caudate, corpus callosum). Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity with each brain volume measure were examined using linear regression, adjusted for age, sex, education, ApoE e4 status, total gray matter atrophy, white matter hyperintensities, hypertension, and glucose. Compared to participants whose both parents died before 85, those with at least one parent surviving to 85 had greater brain volumes in hippocampus, parahippocampal gyrus, inferior temporal lobe, middle temporal lobe, and precentral gyrus in fully adjusted models (Bonferroni corrected p<0.01). There were no significant associations with volumes in dorsolateral prefrontal cortex, putamen or caudate. Parental longevity is associated with preserved brain structure localized in memory- and motor-related cortical regions. These findings support previous reports that parental longevity is associated with better memory and gait with aging.

Dietary Restriction Improves Fitness of Aging Parents But Reduces Fitness of Their Offspring in Nematodes

Dietary restriction (DR) is a well-established intervention to extend lifespan across taxa. Recent studies suggest that DR-driven lifespan extension can be cost-free, calling into question a central tenant of the evolutionary theory of aging. Nevertheless, boosting parental longevity can reduce offspring fitness. Such intergenerational trade-offs are often ignored but can account for the “missing costs” of longevity. Here, we use the nematode Caenorhabditis remanei to test for effects of DR by fasting on fitness of females and their offspring. Females deprived of food for 6 days indeed had increased fecundity, survival, and stress resistance after re-exposure to food compared with their counterparts with constant food access. However, offspring of DR mothers had reduced early and lifetime fecundity, slower growth rate, and smaller body size at sexual maturity. These findings support the direct trade-off between investment in soma and gametes challenging the hypothesis that increased somatic maintenance and impaired reproduction can be decoupled.

Dietary restriction improves fitness of ageing parents but reduces fitness of their offspring

Dietary restriction (DR) is a well-established intervention to extend lifespan across taxa. Recent studies suggest that DR-driven lifespan extension can be cost-free, calling into question a central tenant of the evolutionary theory of ageing. Nevertheless, boosting parental longevity can reduce offspring fitness. Such intergenerational trade-offs are often ignored but can account for the ‘missing costs’ of longevity. Here, we use the nematode Caenorhabditis remanei to test for effects of DR by fasting on fitness of females and their offspring. Females deprived of food for six days indeed had increased fecundity, survival and stress resistance after re-exposure to food compared to their counterparts with constant food access. However, offspring of DR mothers had reduced early and lifetime fecundity, slower growth rate, and smaller body size at sexual maturity. These findings support the direct trade-off between investment in soma and gametes challenging the hypothesis that increased somatic maintenance and impaired reproduction can be decoupled.

Advanced Parental Age at Conception and Sex Affects Mitochondrial DNA Copy Number in Human and Fruit Flies

Aging is a multifactorial trait caused by early as well as late-life circumstances. A society trend that parents deliberately delay having children is of concern to health professionals, for example as advanced parental age at conception increases disease risk profiles in offspring. We here aim to study if advanced parental age at conception affects mitochondrial DNA content, a cross-species biomarker of general health, in adult human twin offspring and in a model organism. We find no deteriorated mitochondrial DNA content at advanced parental age at conception, but human mitochondrial DNA content was higher in females than males, and the difference was twofold higher at advanced maternal age at conception. Similar parental age effects and sex-specific differences in mitochondrial DNA content were found in Drosophila melanogaster. In addition, parental longevity in humans associates with both mitochondrial DNA content and parental age at conception; thus, we carefully propose that a poorer disease risk profile from advanced parental age at conception might be surpassed by superior effects of parental successful late-life reproduction that associate with parental longevity.