Genetics of aging
Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.
The first mutation found to increase longevity in an animal was the age-1 gene in Caenorhabditis elegans. Michael Klass discovered that lifespan of C. elegans could be altered by mutations, but Klass believed that the effect was due to reduced food consumption (calorie restriction).[1] Thomas Johnson later showed that life extension of up to 65% was due to the mutation itself rather than due to calorie restriction,[2] and he named the gene age-1 in the expectation that other genes that control aging would be found. The age-1 gene encodes the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K).
A decade after Johnson's discovery daf-2, one of the two genes that are essential for dauer larva formation,[3] was shown by Cynthia Kenyon to double C. elegans lifespan.[4] Kenyon showed that the daf-2 mutants, which would form dauers above 25 °C (298 K; 77 °F) would bypass the dauer state below 20 °C (293 K; 68 °F) with a doubling of lifespan.[4] Prior to Kenyon's study it was commonly believed that lifespan could only be increased at the cost of a loss of reproductive capacity, but Kenyon's nematodes maintained youthful reproductive capacity as well as extended youth in general. Subsequent genetic modification (PI3K-null mutation) to C. elegans was shown to extend maximum life span tenfold.[5][6]
Long-lived mutants of C. elegans (age-1 and daf-2) were demonstrated to be resistant to oxidative stress and UV light.[7] These long-lived mutants had a higher DNA repair capability than wild-type C. elegans.[7] Knockdown of the nucleotide excision repair gene Xpa-1 increased sensitivity to UV and reduced the life span of the long-lived mutants. These findings support the hypothesis that DNA damage has a significant role in the aging process.[7]
Genetic modifications in other species have not achieved as great a lifespan extension as have been seen for C. elegans. Drosophila melanogaster lifespan has been doubled.[8] Genetic mutations in mice can increase maximum lifespan to 1.5 times normal, and up to 1.7 times normal when combined with calorie restriction.[9]
In yeast, NAD+-dependent histone deacetylase Sir2 is required for genomic silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA). In some species of yeast, replicative aging may be partially caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. ERCs have not been observed in other species (nor even all strains of the same yeast species) of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans (they have not been shown to accumulate in mammals in a similar manner to yeast). Extrachromosomal circular DNA (eccDNA) has been found in worms, flies, and humans. The origin and role of eccDNA in aging, if any, is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies (though, in flies, this finding has not been replicated by other investigators, and the activator of Sir2
RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.
Other genes regulate aging in yeast by increasing the resistance to
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect
Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells, more NAD+ is available and can activate Sir2. Resveratrol, a stilbenoid found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies (the lifespan extension in flies and worms have proved to be irreproducible by independent investigators[10]). It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction, if one accepts that caloric restriction is indeed dependent on Sir2.
According to the GenAge database of aging-related genes, there are over 1800 genes altering lifespan in
The following is a list of genes connected to longevity through research
Podospora | Saccharomyces | Caenorhabditis | Drosophila | Mus |
---|---|---|---|---|
grisea | LAG1 | daf-2 | sod1 | Prop-1 |
LAC1 | age-1/daf-23 | cat1 | p66shc (Not independently verified) | |
pit-1 |
Ghr | |||
RAS1 | daf-18 | mth | mclk1
| |
RAS2 | akt-1/akt-2 | |||
PHB1 | daf-16 | |||
PHB2 | daf-12 | |||
CDC7 |
ctl-1 | |||
BUD1 | old-1 | |||
RTG2 | spe-26 | |||
RPD3 | clk-1 |
|||
HDA1 | mev-1 | |||
SIR2 |
||||
aak-2 | ||||
SIR4-42 | ||||
UTH4 | ||||
YGL023 | ||||
SGS1 | ||||
RAD52 | ||||
FOB1 |
In July
Ned Sharpless and collaborators demonstrated the first in vivo link between
See also
References
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- PMID 8056303.
- ^ S2CID 4332206.
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- ^ . Epub 2008 Jan 18. PMID: 18203746; PMCID: PMC2275101
- S2CID 28565101.
- S2CID 4379930.
- ^ S2CID 1780784.
- ^ a b "GenAge database". Retrieved 26 February 2011.
- ^ PMID 32678081. Text and images are available under a Creative Commons Attribution 4.0 International License.
- ^ "Blood iron levels could be key to slowing ageing, gene study shows". phys.org. Retrieved 18 August 2020.
- PMID 15520862.
- PMID 23242215.
- PMID 22048312.
- PMID 25754370.
External links
- Human Ageing Genomic Resources, a collection of databases and tools designed to help researchers study the genetics of human aging
- The NetAge Database, an online database and network analysis tools for biogerontological research