Over the past 20 years, a large amount of data has been generated to cover the genetics, epigenetics, transcriptomics, proteomics, and the many varied aspects of the metabolism of long-lived individuals. Very little has been found when it comes to genetic variants associated with longevity - or rather every study produces associations, and then those association near all fail to replicate. The few genetic associations with longevity that hold up on multiple study populations and appear otherwise robust have small effect sizes.
Metabolism and immune function are perhaps more interesting, however. Long-lived individuals are long-lived in large part because they have a less degraded, more functional metabolism and immune system. Otherwise they would already be dead. It isn't clear whether the wealth of data pointing to this less impacted function of metabolism and immune system will at the end of the day provide novel, useful answers to the question of why some people achieve this outcome while others do not.
Clearly lifestyle is important, but there remains a substantial variation in outcomes between individuals with similarly healthy lifestyles. It is possible that this variation is driven by thousands of individually tiny contributions, summing to a different aggregate effect for each person, in which case there will be little of use to be found in the biochemistry of long-lived individuals when it comes to a basis for the creation of therapies to slow aging.
[Publicity Materials] Factors involved in human healthy aging: insights from longevity individuals
Long-lived individuals (LLIs), defined as individuals surviving beyond 90 years, exhibit distinct characteristics such as reduced morbidity, delayed onset of chronic diseases, and preserved physiological functions. Key nuclear genomic variants include APOE ε2 (protective against cardiovascular disease and Alzheimer's), FOXO3A (linked to oxidative stress resistance and DNA repair), and SIRT6 (involved in genome maintenance). Mitochondrial haplogroups like J and D are associated with reduced oxidative stress, while telomere maintenance genes (hTERT, TERC) ensure chromosome stability. However, genome-wide association studies (GWAS) highlight APOE and FOXO3A as the most consistently linked genes across populations, underscoring their pivotal roles.
Epigenetic mechanisms bridge genetics and environment. DNA methylation patterns in LLIs show delayed age-related methylation loss, particularly in heterochromatin regions, which may stabilize genome integrity. Noncoding RNAs, such as miR-363* and lncRNAs THBS1-IT1/THBS1-AS1, regulate cellular senescence and gene expression, contributing to healthy aging. These epigenetic signatures correlate with younger biological age and reduced disease risk in LLIs and their offspring.
Metabolic profiles in LLIs are characterized by favorable lipid metabolism (low LDL cholesterol, high HDL), reduced insulin resistance, and enhanced antioxidant capacity. Endocrine factors like low thyroid hormone levels and preserved sex hormones (estradiol in females, testosterone in males) play protective roles.
Immune system alterations in LLIs include reduced chronic inflammation ("inflammaging") and preserved immune cell function. Centenarians exhibit lower IL-6 levels, higher TGF-β and IL-10 (anti-inflammatory cytokines), and maintained T-cell proliferation and natural killer cell activity. The balance between pro-inflammatory Th17 cells and regulatory T cells (Tregs) shifts toward anti-inflammatory states, contributing to disease resistance. Environmental and lifestyle factors are equally critical. Gut microbiota in LLIs features increased diversity and enrichment of health-promoting taxa like Akkermansia muciniphila and Bifidobacterium, which enhance gut barrier function and produce anti-aging metabolites.
[Paper] Factors involved in human healthy aging: insights from longevity individuals
The quest to decipher the determinants of human longevity has intensified with the rise in global life expectancy. Long-lived individuals (LLIs), who exceed the average life expectancy while delaying age-related diseases, serve as a unique model for studying human healthy aging and longevity. Longevity is a complex phenotype influenced by both genetic and non-genetic factors. This review paper delves into the genetic, epigenetic, metabolic, immune, and environmental factors underpinning the phenomenon of human longevity, with a particular focus on LLIs, such as centenarians. By integrating findings from human longevity studies, this review highlights a diverse array of factors influencing longevity, ranging from genetic polymorphisms and epigenetic modifications to the impacts of diet and physical activity. As life expectancy grows, understanding these factors is crucial for developing strategies that promote a healthier and longer life.
View the full article at FightAging
