All common complex diseases increase with age but it is not clear whether aging is the cause or effect of such diseases. Studies of the genetics of human aging usually use lifespan (age at death), longevity (a specific advanced age), exceptional longevity (a specific exceptional age), or healthy aging (old age and health combined). Longevity studies focus on long-lived individuals like nonagenarians and centenarians, a simpler observable characteristic (phenotype) compared with healthy aging studies which can involve different definitions of healthy aging with reference to diseases, cognition and mobility. Other studies that are related to longevity are concerned with fundamental biological processes of aging such as cellular senescence.
The oldest person recorded was 122 years old, a French woman named Jeanne Calment, who died in 1997. Since there are so few centenarians, good data on which to base theories on the limits of lifespan have been difficult to acquire. A research study published in Science in 2018 suggests that a maximum lifespan for humans has not been reached and that human longevity is increasing. The study by Italian and European researchers points to a leveling off or in some cases a decrease in risk of death for humans after the age of 105. The study looked at mortality in 3,836 Italians aged 105 or older between the years 2009-2015.
In animal models, healthy lifespan has been expanded with dietary restriction and genetic manipulation, and several molecular pathways in lifespan regulation have been identified. Turning down nutrient-sensing pathways like insulin/insulin-like growth factor (IGF-1) signaling and target of rapamycin (TOR) signaling have expanded lifespan. In rodents and monkeys, diets restricting glucose, fat or protein decreased risk of cancer and metabolic disease, which extended lifespan. As opposed to animal model systems where single gene mutations have major effects on life extension, human longevity is more likely a complex trait. Heritability studies have compared concordance of lifespan in identical twins (monozygous) which have nearly identical genomes, and fraternal twins (dizygous) whose genomes are as alike as any siblings and estimated the genetic contribution to lifespan variation was 25-30% genetic.
The survival benefit of long-lived individuals and their family members can be found at both high and middle age. In middle age, the offspring of long-loved siblings have been shown to have lower prevalence of diabetes, myocardial infarction, hypertension, cardiovascular disease and cancer compared with their partners who share a common environment. Many of these results have come from the Leiden Longevity Study (LLS). Specific markers of glucose and lipid metabolism and insulin sensitivity preservation are associated with longevity in LLS studies.
Individuals who live exceptionally long tend to also be healthy for a large portion of their lives. This was demonstrated in a study that looked at the health of supercentenarians (aged 110-119), semisupercentenarians (aged 105-109), centenarians (in this context aged 100-104), nonagenarians, and younger controls found a greater delay in onset of major disease in older groups.
Longevity has a low prevalence of 1 centenarian in 5000 individuals, making it difficult to detect rare gene variants that contribute to extreme longevity using genome wide association studies (GWAS).Candidate gene approaches look for associations between longevity and pre-specified genes of interest. WRN and LMNA are genes that have been associated with longevity in both approaches and they are associated with two human syndromes that show accelerated aging characteristics, Werner syndrome and Hutchinson-Gilford progeria syndrome. Some variants of these genes have a positive effect on lifespan while others cause premature aging.
Small nucleotide polymorphisms (SNPs) in sirtuins (SIRT1 and SIRT3) have been associated with human longevity, fitting with the lifespan effects of these genes in model organisms. Different sirtuin SNPS were associated with overall reduced mortality, reduced mortality in obese individuals, better glucose tolerance and telomere length maintenance. Female and male longevity associations were often different.
Variants in the genes FOXO1, AKT1, APOE have been associated with longevity in the LLS. Thyroid-stimulating hormone level and TSHR gene variation have been associated with longevity in the Ashkenazi Jewish Centenarian Study. Other studies have connected longevity with certain variations in RNA-editing genes.
The LongevityMap is a database of genes, loci and variants associated with human longevity and healthy aging which has contributions and curation from scientists internationally. GenAge is a database of longevity related genes studied in model organisms and human progeroid syndromes which are syndromes that mimic physiological aging. Some genes with variants associated with longevity may be targeted for drug development.
The roles of the IGFs, their receptors and other proteins in the pathway seem to be important in skeletal muscle aging in mouse models and human skeletal muscle cells. Evidence suggests that IGF-I and downstram signaling pathways are needed to maintain skeletal muscle throughout the lifespan. Reductions in IGF-I activity with age are linked to reductions in SkM size and function. On the other hand, in model organisms reduced signalling through the IIS pathway is also associated with increased lifespan.
TOR (target of rapamycin) or mTOR (mammalian target of rapamycin) is both a key regulator of skeletal muscle growth and is also associated with human longevity. In the elderly, mTOR becomes less responsive to contraction-induced activation through resistance exercise and the elderly have an impaired activity of mTOR in response to amino acid feeding, known as anabolic resistance. However outside of muscle, rapamycin-induced inhibition of mTOR can increase lifespan in model organisms and rapamycin can reduce certain age-related pathogies.
Proteostasis, the maintenance of protein quality, is important for the health and longevity of the cell. By culling misfolded and damaged proteins proteostasis helps maintain a supply of good quality protein inside living systems. Disruption of proteostasis is associated with aging in the model organism Caenorhabditis elegans, and stress. HSF-1 and DAF-16/FOXO can modulate proteostasis and thier activities are implicated in healthy aging and long-lived mutants in model organisms.
Degradation and stress on the cytoskeleton of cells as they age affects extracellular signals passing into and out of the cell. Cells also communicate their internal status such as DNA damage, oncogene activation and proteomic dysregulation to neighboring cells by the senescence-associated secretory phenotype (SASP). SASP may play a role in tumor formation, aging and age-related pathologies like neurodegenerative diseases.
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