The impact of mitochondrial DNA on human lifespan: A view from studies on centenarians

Abstract

The role of inherited and somatic mutations of mitochondrial DNA (mtDNA) in aging and longevity is complex and highly controversial, owing to its peculiar genetics, including the phenomenon of heteroplasmy. Most of the data on mtDNA and longevity have been obtained on humans and particularly on centenarians, i. e., people who escaped or delayed the major age-related pathologies and reached the extreme limit of human lifespan. In this review we summarize the most recent advances in this field that suggest a consistent role in human longevity of both germ-line inherited and somatically acquired mutations. The particular case of the association with longevity of the somatic C150T mutation is extensively discussed, challenging the tenet that mtDNA mutations are basically detrimental. We also stress several limitations of our present knowledge, regarding the difficulty in extrapolating to humans the results obtained in animal models, owing to a variety of biological differences, including the very limited genetic variability of mtDNA in the strains used in laboratory experiments. The use of high-throughput technologies and the extensive analysis, possibly at the single cell level, of different tissues and cell types derived from the same individual will help in disentangling the complexity of mtDNA in aging and longevity.

Is the ACE I/D polymorphism associated with extreme longevity? A study on a Spanish cohort

“…1 These people are the survival tail of the population since they escaped diseases of the preantibiotic era, and have avoided or postponed age-related diseases and their fatal consequences. 2 The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the maintenance of cardiovascular homeostasis. One important gene of the RAAS that has received attention with regards to its possible role in longevity is the gene encoding the angiotensin-converting enzyme (ACE).…”

Human longevity and 11p15.5: a study in 1321 centenarians

“…20 A replication study was then designed for SIRT3: eight SNPs were tested in a French sample (546 cases -age range 99 -106 years old, mean 103.1, and 315 controls -age range 18 -70 years old, mean 51.2) at CEPH in Paris. None of the earlier findings were confirmed in this analysis.…”

Are centenarians genetically predisposed to lower disease risk?

“…Our findings also are limited by the fact that we did not study genetic susceptibility to other types of diseases, notably infectious diseases. This is an important consideration because centenarians have escaped diseases of the pre-antibiotic era (Salvioli et al 2008). Nevertheless, it must be kept in mind that it is difficult to account for all the candidate genetic polymorphisms that can be potentially associated with disease risk and thus survival.…”

“…These people have postponed age-related diseases and their fatal consequences (Salvioli et al 2008), and the onset of disability is generally delayed until they are well into their mid-90s (Terry et al 2008;Christensen et al 2008). Both environmental and genetic factors contribute to the complex phenotype of exceptional longevity.…”