Introduction Heritability of human longevity has been estima
Heritability of human longevity has been estimated as 15–40% [, , , , , , , , ], although recent data from 5.3 million family trees of up to 13 million members generated from 86 million public profiles on an online genealogy database obtained an estimate of 16% . The heritability of longevity may, however, depend on how extreme the survival probabilities used to define longevity are . At younger ages, environmental factors such as infectious disease, rare conditions and externally inflicted trauma are the main causes of death. By old age (circa 70 years), individuals have partly escaped the most common causes of death in middle age, such as cancer and cardiovascular disease. Beyond age 70 the genetic component becomes increasingly important, influencing to a variable extent most common polygenic conditions that ramp up from middle-age onwards. In very old age (> 90 years) specific longevity KRN 7000 chemicals emerge from the shadows and dominate over environmental influences in lifespan determination. Recent data from the Netherlands suggested paternal transmission of longevity is stronger than maternal transmission .
Molecular genetic basis of longevity
Transcriptomics The transcriptome of centenarians differs from that of septuagenarians . In centenarians 1721 genes were differentially expressed compared with septuagenarians and young people. The most statistically significant associations with biological processes were immune response, followed by cell adhesion and MHC class 1 receptor activity, transport processes, antigen processing and presentation of peptide antigen via MHC class 1, response to drug, ion transport, signal transduction, cell surface receptor linked signaling pathway, small GTPase mediated signal transduction, intracellular signaling pathway, response to wounding, presentation of endogenous peptide antigen. Response to hypoxia, apoptosis, protein transport, T cell activation and processes integral to the plasma membrane . Sub-network analysis converged on 6 genes – interferon-γ gene, IFNG (Fig. 4) – T-cell receptor gene, TCR; tumor necrosis factor gene, TNF; SP1 transcription factor gene, SP1; TGF-β1 gene, TGFB1; and interleukin 32 gene, IL32 – to influence B-cell lymphoma-extra large (Bcl-xL) gene, BCL2L1, Fas and Fas ligand, all involved in the control of apoptosis – Bcl-xL by inhibiting the intrinsic, mitochondrial pathway to apoptosis, and Fas and FasL by controlling the extrinsic pathway to apoptosis. As well as being involved in apoptosis, Bcl-xL is involved in mitochondrial damage protection , control of mitochondrial respiration , modulation of the immune response  and DNA repair , all of which are associated with healthy aging. Genes upregulated in centenarians tended to be downregulated in septuagenarians, consistent with activation of those networks in exceptional aging. In Spanish and Sardinian cohorts, BCL2L1 mRNA expression and protein were higher in centenarians than in septuagenarians, but were similar to young individuals, suggesting a major role in healthy aging . In support, transfection of Bcl-xL into mouse embryo fibroblasts and septuagenarian lymphocytes suppressed cell cycle inhibitors, increased cell proliferation, protected against oxidative damage, and delayed the accumulation of senescent cells. A constitutively active mutant of the Caenorhabditis elegans BCL2L1 ortholog, ced-9, increased survival . These findings revealed an important role for BCL2L1 in human aging. A transcriptomic prediction model was developed from whole-blood gene expression data for 14,983 individuals of European ancestry from 6 independent cohorts . The 1497 genes differentially expressed with chronological age will be discussed in the epigenetics section below. RNA profiles of young vs. old human muscle were able to distinguish the age of multiple tissue types . Regulators of the 150 genes identified were identified by reverse genetics and pharmacological methods . Rapamycin perturbed the healthy aging gene expression signature. A degree of direct coordination and a link with mTOR activity pointed to a link between a healthy neuromuscular age biomarker and a major axis of lifespan .