Specific differences and novel key regulatory genes of sex in influencing exceptional longevity phenotypes.

BACKGROUND AND AIMS: Although the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity phenotypes remain largely unknown. Therefore, we performed transcriptome sequencing of peripheral blood samples to explore regulatory mechanisms of healthy longevity by incorporating sex data. METHODS: We selected 34 exceptional longevity (age: 98.26 ± 2.45 years) and 16 controls (age: 52.81 ± 9.78) without advanced outcomes from 1363 longevity and 692 controls recruited from Nanning of Guangxi for RNA sequencing 1. The transcriptome sequencing 1 data of 50 samples were compared by longevity and sex to screen differentially expressed genes (DEGs). Then, 121 aging samples (40-110 years old) without advanced outcomes from 355 longevity and 294 controls recruited from Dongxing of Guangxi were selected for RNA sequencing 2. The genes associated with aging from the transcriptome sequencing 2 of 121 aging samples were filtered out. Finally, the gender-related longevity candidate genes and their possible metabolic pathways were verified by cell model of aging and a real-time polymerase chain reaction (RT-PCR). RESULTS: Metabolism differs between male and female and plays a key role in longevity. Moreover, the principal findings of this study revealed a novel key gene, UGT2B11, that plays an important role in regulating lipid metabolism through the peroxisome proliferator activated receptor gamma (PPARG) signalling pathway and ultimately improving lifespan, particularly in females. CONCLUSION: The findings suggest specific differences in metabolism affecting exceptional longevity phenotypes between the sexes and offer novel therapeutic targets to extend lifespan by regulating lipid homeostasis.

Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging.

The transition from ordered to noisy is a significant epigenetic signature of aging and age-related disease. As a paradigm of healthy human aging and longevity, long-lived individuals (LLI, >90 years old) may possess characteristic strategies in coping with the disordered epigenetic regulation. In this study, we constructed high-resolution blood epigenetic noise landscapes for this cohort by a methylation entropy (ME) method using whole genome bisulfite sequencing (WGBS). Although a universal increase in global ME occurred with chronological age in general control samples, this trend was suppressed in LLIs. Importantly, we identified 38,923 genomic regions with LLI-specific lower ME (LLI-specific lower entropy regions, for short, LLI-specific LERs). These regions were overrepresented in promoters, which likely function in transcriptional noise suppression. Genes associated with LLI-specific LERs have a considerable impact on SNP-based heritability of some aging-related disorders (e.g., asthma and stroke). Furthermore, neutrophil was identified as the primary cell type sustaining LLI-specific LERs. Our results highlight the stability of epigenetic order in promoters of genes involved with aging and age-related disorders within LLI epigenomes. This unique epigenetic feature reveals a previously unknown role of epigenetic order maintenance in specific genomic regions of LLIs, which helps open a new avenue on the epigenetic regulation mechanism in human healthy aging and longevity.