Effect of FOXO3 and Air Pollution on Cognitive Function: A Longitudinal Cohort Study of Older Adults in China from 2000 to 2014

Forkhead Box O 3 (FOXO3) genotype is strongly associated with human longevity and may be protective against neurodegeneration. Air pollution is a risk factor for cognitive decline and dementia. We aimed to study the individual and combined effects of FOXO3 and air pollution on cognitive function in a large prospective cohort with up to 14 years of follow-up. We measured cognitive function and impairment using the Mini-Mental State Examination (MMSE). We used tagging SNPs rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene, of which roughly half of the population had the longevity associated polymorphism. We matched annual average fine particulate matter (PM2.5) concentrations within 1 km^2 grid. We conducted cross-sectional and longitudinal analyses using multivariable linear and logistic regression models and generalized estimating equation. At baseline, carriers of the longevity associated homozygous minor alleles of FOXO3 SNPs had a higher MMSE score than the carriers of homozygous major alleles. In the longitudinal follow-up, carriers of FOXO3 homozygous minor alleles had lower odds of cognitive impairment compared to non-carriers. Higher PM2.5 was associated with a lower MMSE score and higher odds of cognitive impairment. The positive effects of FOXO3 were the strongest in females, older people, and residents in areas with lower air pollution.

Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases

Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people. Emerging evidence indicates that FOXO3 plays a critical role in vascular aging. FOXO3 inactivation is implicated in several aging-related vascular diseases. In experimental studies, FOXO3-engineered human ESC-derived vascular cells improve vascular homeostasis and delay vascular aging. The purpose of this review is to explore how FOXO3 regulates vascular aging and its crucial role in aging-related vascular diseases.

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.

The genomics of exceptional longevity in rockfishes refine genetic foundations of human lifespan variation

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, ranging in longevity from 11 to over 205 years. Shifts in rockfish longevity occurred multiple times independently, and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent restricted evolution in long-lived lineages, encompassing established aging regulators such as insulin-signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a novel pathway modulating longevity. Further, these genes were used to refine human longevity GWAS, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with the 99th percentile of human longevity, independently validating its importance and conservation. This evolutionary intersection highlights a novel, conserved genetic architecture that associates with the evolution of longevity across vertebrates and provides actionable targets for research into lifespan and healthspan modulation.

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in the regulation of aging and metabolism. Targeted sequencing identified a SIRT6 allele containing two linked substitutions (N308K/A313S) as enriched in Ashkenazi Jewish (AJ) centenarians as compared to AJ control individuals. Characterization of this SIRT6 (centSIRT6) allele demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double strand break repair, and more robust cancer cell killing compared to the wild type. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

Long-lived humans have a unique plasma sphingolipidome

A species-specific lipidome profile is an inherent feature linked to longevity in the animal kingdom. However, there is a lack of lipidomic studies on human longevity. Here we use mass spectrometry based lipidomics to detect and quantify 151 sphingolipid molecular species and use these to define a phenotype of healthy humans with exceptional lifespan. Our results demonstrate that this profile specifically comprises a higher content of complex glycosphingolipids (hexosylceramides and gangliosides), and lower levels of ceramide species from the de novo pathway, sphingomyelin and sulfatide; while for ceramide-derived signaling compounds, their content remains unchanged. Our findings suggest that structural glycosphingolipids may be more relevant to achieve the centenarian condition than signaling sphingolipids.

Analysis of Cell and Molecular Phenotypes of a Highly Replicated Longevity-Associated FOXO3 Variant in Older Adults

Aging demographics in the US, and other industrialized nations, are resulting in rapidly increasing health care costs from age-related diseases. New therapeutic interventions to extend healthspan in older adults requires understanding connections between basic aging biology and human longevity factors. Using clinical samples from the Kuakini Honolulu Heart Program (HHP) and their Offspring, we are examining potential links between molecular and cellular mechanisms of aging and the longevity associated FOXO3 genotype (carriage of SNP rs2802292 “G” allele). Telomere dynamics in leucocytes (LTL) have shown strong correlation with multiple lifestyle and health factors. We previously demonstrated a significant protective relation between FOXO3 longevity genotype and LTL in a cross-sectional study. Now we are assessing a longitudinal relation, at three time points over 20+ years, in older men. We are also exploring stem cell frequency and differentiation capacity in neurological and peripheral blood samples to assess FOXO3 genotype and human cell dynamics.

The Interplay Between Stress Related Genes and Its Role in Human Longevity: Insights for Translational Studies

Human lifespan is a multifactorial trait resulted from complicated interplay among many genetic and environmental factors. Despite substantial progress in clarifying many aspects of lifespan’ variability the mechanism of its multifactorial regulation remains unclear. In this paper we investigate the role of genes from integrated stress response (ISR) pathway in such regulation. Experimental studies showed that persistent cellular stress may result in cellular senescence (for proliferating cells), or in apoptosis (for post-mitotic cells) which may affect health and lifespan in laboratory animals. These studies also showed which ISR genes are likely to interplay to produce joint effects on these traits. Note that in humans, the interplay between these genes does not necessarily influence these traits. This is because biological mechanisms regulating these traits in laboratory animals and humans may differ. This means that, when possible, the experimentally detected connections promising for human applications, should be verified using available human data before their testing in expensive clinical trials. In this paper we used HRS data to test connection between SNPs from the EIF2AK4 gene that senses cellular stress signals and the DDIT3 gene from the apoptosis regulation part of the ISR. We found genome wide significant associations between interacting SNPs from these genes and longevity. This result shows that available human data may be successfully used for making important steps in translation of experimental research findings towards their application in humans. Following this strategy may increase efficiency of clinical trials aiming to find appropriate medications to promote human health and longevity.

FOXO3, Telomere Dynamics, and Healthy Brain Aging: A COBRE Study

Human longevity is linked to genetic, cellular, and other complex biological and psychosocial traits. Aging is typically accompanied by gradual brain atrophy and cognitive decline, but the mechanisms are unclear. Cellular aging, characterized by telomere shortening and altered telomerase activity, is related to mortality and brain aging. Decelerated brain aging is associated with greater peripheral blood leukocyte telomere length (LTL) and, we hypothesize, may be linked to FOXO3 genotype. We will use MRI to assess brain structure and function cross-sectionally in 100 Kuakini Honolulu Heart Program Offspring. Atrophy and disrupted functional connectivity, markers of brain aging, will be examined in relation to FOXO3 and LTL. Associations between brain structural and functional differences, FOXO3 genotype and LTL will be investigated over a wide range of ages, controlling for other biological and psychosocial factors. Results may provide insight into mechanisms influencing the rate of brain aging, and may eventually extend human healthspan.