Genetics of aging

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Many life span influencing genes affect the rate of DNA damage or DNA repair. Dnadamage.png
Many life span influencing genes affect the rate of DNA damage or DNA repair.

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

Contents

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 (77 °F) would bypass the dauer state below 20 °C (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 resveratrol does not reproducibly increase lifespan in either species. [10] ) Whether the Sir2 homologues in higher organisms have any role in lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.

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 oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.

In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies, and the growth hormone/IGF1 axis in mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to niacin, nicotinamide is removed, inhibiting the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels. It is not known, however, whether these mechanisms also exist in humans, since there are obvious differences in biology between humans and model organisms.

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 model organisms: 838 in the soil roundworm ( Caenorhabditis elegans ), 883 in the bakers' yeast ( Saccharomyces cerevisiae ), 170 in the fruit fly ( Drosophila melanogaster ) and 126 in the mouse ( Mus musculus ). [11]

The following is a list of genes connected to longevity through research [11] on model organisms:

PodosporaSaccharomycesCaenorhabditisDrosophilaMus
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
"Healthspan, parental lifespan, and longevity are highly genetically correlated." Healthspan, parental lifespan, and longevity are highly genetically correlated.webp
"Healthspan, parental lifespan, and longevity are highly genetically correlated."

In July 2020 scientists, using public biological data on 1.75 m people with known lifespans overall, identify 10 genomic loci which appear to intrinsically influence healthspan, lifespan, and longevity – of which half have not been reported previously at genome-wide significance and most being associated with cardiovascular disease – and identify haem metabolism as a promising candidate for further research within the field. Their study suggests that high levels of iron in the blood likely reduce, and genes involved in metabolising iron likely increase healthy years of life in humans. [13] [12]

Ned Sharpless and collaborators demonstrated the first in vivo link between p16-expression and lifespan. [14] They found reduced p16 expression in some tissues of mice with mutations that extend lifespan, as well as in mice that had their lifespan extended by food restriction. Jan van Deursen and Darren Baker in collaboration with Andre Terzic at the Mayo Clinic in Rochester, Minn., provided the first in vivo evidence for a causal link between cellular senescence and aging by preventing the accumulation of senescent cells in BubR1 progeroid mice. [15] In the absence of senescent cells, the mice's tissues showed a major improvement in the usual burden of age-related disorders. They did not develop cataracts, avoided the usual wasting of muscle with age. They retained the fat layers in the skin that usually thin out with age and, in people, cause wrinkling. A second study led by Jan van Deursen in collaboration with a team of collaborators at the Mayo Clinic and Groningen University, provided the first direct in vivo evidence that cellular senescence causes signs of aging by eliminating senescent cells from progeroid mice by introducing a drug-inducible suicide gene and then treating the mice with the drug to kill senescent cells selectively, as opposed to decreasing whole body p16. [16] Another Mayo study led by James Kirkland in collaboration with Scripps and other groups demonstrated that senolytics, drugs that target senescent cells, enhance cardiac function and improve vascular reactivity in old mice, alleviate gait disturbance caused by radiation in mice, and delay frailty, neurological dysfunction, and osteoporosis in progeroid mice. Discovery of senolytic drugs was based on a hypothesis-driven approach: the investigators leveraged the observation that senescent cells are resistant to apoptosis to discover that pro-survival pathways are up-regulated in these cells. They demonstrated that these survival pathways are the "Achilles heel" of senescent cells using RNA interference approaches, including Bcl-2-, AKT-, p21-, and tyrosine kinase-related pathways. They then used drugs known to target the identified pathways and showed these drugs kill senescent cells by apoptosis in culture and decrease senescent cell burden in multiple tissues in vivo. Importantly, these drugs had long term effects after a single dose, consistent with removal of senescent cells, rather than a temporary effect requiring continued presence of the drugs. This was the first study to show that clearing senescent cells enhances function in chronologically aged mice. [17]

Genetically determined DNA repair capability and aging

The genetically determined capability to repair DNA damage appears to be a key aging factor in comparisons of several species of birds and animals. When the rate of accumulation of DNA damage (double-strand breaks) in the leukocytes of dolphins, goats, reindeer, American flamingos, and griffon vultures was compared to the longevity of individuals of these different species, it was found that the species with longer lifespans have slower accumulation of DNA damage. [18] The activity of the enzyme PARP1, employed in several DNA repair process, was compared in thirteen different mammalian species and its activity was found to correlate with the maximum lifespan of the species. [19] In humans, genetically determined DNA repair capability appears to influence lifespan. Lymphoblastoid cell lines established from blood samples of humans who lived past 100 years (centenarians) were found to have a significantly higher activity of the DNA repair protein Poly (ADP-ribose) polymerase (PARP) than cell lines from younger individuals (20 to 70 years old). [20]

Herdles for increasing longevity

Paternal age effect

This section is an excerpt from Paternal age effect § Life expectancy.[ edit ]

A 2008 paper found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18). [21] Although the relative mortality rates were higher, the absolute numbers were low, because of the relatively low occurrence of genetic abnormality. The study has been criticized for not adjusting for maternal health, which could have a large effect on child mortality. [22] The researchers also found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors. [23]

In 2012, a study showed that greater age at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has effects on health and mortality, this may have effects on health and the rate of aging in these offspring. The authors speculated that this effect may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts. [24]

See also

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<span class="mw-page-title-main">Life extension</span> Concept of extending human lifespan by improvements in medicine or biotechnology

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled biological limit of around 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

Maximum life span is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between birth and death, provided circumstances that are optimal to that member's longevity.

The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.

The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”

<span class="mw-page-title-main">COQ7</span> Protein-coding gene in humans

Mitochondrial 5-demethoxyubiquinone hydroxylase, also known as coenzyme Q7, hydroxylase, is an enzyme that in humans is encoded by the COQ7 gene. The clk-1 (clock-1) gene encodes this protein that is necessary for ubiquinone biosynthesis in the worm Caenorhabditis elegans and other eukaryotes. The mouse version of the gene is called mclk-1 and the human, fruit fly and yeast homolog COQ7.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Leonard Pershing Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, roundworms, and mice. He is a Novartis Professor of Biology at the Massachusetts Institute of Technology.

<span class="mw-page-title-main">Cynthia Kenyon</span> US molecular biologist

Cynthia Jane Kenyon is an American molecular biologist and biogerontologist known for her genetic dissection of aging in a widely used model organism, the roundworm Caenorhabditis elegans. She is the vice president of aging research at Calico Research Labs, and emeritus professor of biochemistry and biophysics at the University of California, San Francisco (UCSF).

<span class="mw-page-title-main">SOD2</span> Enzyme

Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6. A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants. This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer.

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

Extrachromosomal rDNA circles are pieces of extrachromosomal circular DNA (eccDNA) derived from ribosomal DNA (rDNA). Initially found in baker's yeast, these self-replicating circles are suggested to contribute to their aging and found in their aged cells. Like ordinary eccDNA, they are created by intra-molecular homologous recombination of the chromosome. The process for intra-molecular homologous recombination is independent of chromosomal replication. The de novo generated circles had exact multiples of tandem copies of 2-kb fragments from cosmid templates. The tandem organization is essential to circle formation. Looping out of organized ribosomal genes in intergenic nontranscribed spacers yielded either large or small repeat circles dependent on large or short repeats of the spacer.

<span class="mw-page-title-main">Daf-16</span> Ortholog

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.

David Gems is a British geneticist who studies the biology and genetics of ageing (biogerontology). He is Professor of Biogerontology at the Research Department of Genetics, Evolution and Environment, University College London and he is a co-founder and Research Director of the UCL Institute of Healthy Ageing. His work concerns understanding the underlying causes of aging. His research laboratory tests theories of aging and develops new ones using a short-lived animal model C. elegans.

<span class="mw-page-title-main">Biomarkers of aging</span> Type of biomarkers

Biomarkers of aging are biomarkers that could predict functional capacity at some later age better than chronological age. Stated another way, biomarkers of aging would give the true "biological age", which may be different from the chronological age.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, ribosomal DNA (rDNA), and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

In biogerontology, the disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by British biologist Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

References

  1. ↑ Klass MR (1983). "A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results". Mechanisms of Ageing and Development. 22 (3–4): 279–286. doi:10.1016/0047-6374(83)90082-9. PMID   6632998. S2CID   6870538.
  2. ↑ Friedman DB, Johnson TE (1988). "A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility" (PDF). Genetics . 118 (1): 75–86. doi:10.1093/genetics/118.1.75. PMC   1203268 . PMID   8608934.
  3. ↑ Gottlieb S, Ruvkun G (1994). "daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans". Genetics . 137 (1): 107–120. doi:10.1093/genetics/137.1.107. PMC   1205929 . PMID   8056303.
  4. 1 2 Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993). "A C. elegans mutant that lives twice as long as wild type". Nature . 366 (6454): 461–4. Bibcode:1993Natur.366..461K. doi:10.1038/366461a0. PMID   8247153. S2CID   4332206.
  5. ↑ Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008). "Remarkable longevity and stress resistance of nematode PI3K-null mutants". Aging Cell. 7 (1): 13–22. doi: 10.1111/j.1474-9726.2007.00348.x . PMID   17996009. S2CID   2470599.
  6. ↑ Shmookler Reis RJ, Bharill P, Tazearslan C, Ayyadevara S (2009). "Extreme-longevity mutations orchestrate silencing of multiple signaling pathways". Biochimica et Biophysica Acta (BBA) - General Subjects. 1790 (10): 1075–83. doi:10.1016/j.bbagen.2009.05.011. PMC   2885961 . PMID   19465083.
  7. 1 2 3 Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B (March 2008). "Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans". Nucleic Acids Res. 36 (4): 1380–9. doi:10.1093/nar/gkm1161. PMC   2275101 . PMID   18203746.
  8. ↑ Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (1988). "A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function". Science . 292 (5514): 107–110. doi:10.1126/science.1057987. PMID   11292875. S2CID   28565101.
  9. ↑ Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001). "Extending the lifespan of long-lived mice" (PDF). Nature . 414 (6862): 412. doi: 10.1038/35106646 . hdl:2027.42/62803. PMID   11719795. S2CID   4379930.
  10. 1 2 Bass TM; Weinkove D; Houthoofd K; Gems D; Partridge L (October 2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans". Mechanisms of Ageing and Development. 128 (10): 546–552. doi:10.1016/j.mad.2007.07.007. PMID   17875315. S2CID   1780784.
  11. 1 2 "GenAge database" . Retrieved 26 February 2011.
  12. 1 2 Timmers, Paul R. H. J.; Wilson, James F.; Joshi, Peter K.; Deelen, Joris (16 July 2020). "Multivariate genomic scan implicates novel loci and haem metabolism in human ageing". Nature Communications. 11 (1): 3570. Bibcode:2020NatCo..11.3570T. doi: 10.1038/s41467-020-17312-3 . PMC   7366647 . PMID   32678081. CC-BY icon.svg Text and images are available under a Creative Commons Attribution 4.0 International License.
  13. ↑ "Blood iron levels could be key to slowing ageing, gene study shows". phys.org. Retrieved 18 August 2020.
  14. ↑ Krishnamurthy, J; Torrice, C; Ramsey, MR; Kovalev, GI; Al-Regaiey, K; Su, L; Sharpless, NE (2004). "Ink4a/Arf expression is a biomarker of aging". J. Clin. Invest. 114 (9): 1299–1307. doi:10.1172/JCI22475. PMC   524230 . PMID   15520862.
  15. ↑ Baker DJ; Dawlaty MM; Wijshake T; Jeganathan KB; Malureanu L; van Ree JH; Crespo-Diaz R; Reyes S; Seaburg L; Shapiro V; Behfar A; Terzic A; van de Sluis B; van Deursen JM (January 2013). "Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan". Nat Cell Biol. 15 (1): 96–102. doi:10.1038/ncb2643. PMC   3707109 . PMID   23242215.
  16. ↑ Baker, D.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.; Childs, B.; van de Sluis, B.; Kirkland, J.; van Deursen, J. (10 November 2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature. 479 (7372): 232–6. Bibcode:2011Natur.479..232B. doi:10.1038/nature10600. PMC   3468323 . PMID   22048312.
  17. ↑ Zhu, Y; Tchkonia, T; Pirtskhalava, T; Gower, AC; Ding, H; Giorgadze, N; Palmer, AK; Ikeno, Y; Hubbard, GB; Lenburg, M; O'Hara, SP; LaRusso, NF; Miller, JD; Roos, CM; Verzosa, GC; LeBrasseur, NK; Wren, JD; Farr, JN; Khosla, S; Stout, MB; McGowan, SJ; Fuhrmann-Stroissnigg, H; Gurkar, AU; Zhao, J; Colangelo, D; Dorronsoro, A; Ling, YY; Barghouthy, AS; Navarro, DC; Sano, T; Robbins, PD; Niedernhofer, LJ; Kirkland, JL (9 March 2015). "The Achilles' heel of senescent cells: from transcriptome to senolytic drugs". Aging Cell. 14 (4): 644–658. doi:10.1111/acel.12344. PMC   4531078 . PMID   25754370.
  18. ↑ Whittemore K, Martínez-Nevado E, Blasco MA (November 2019). "Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals". Aging (Albany NY). 11 (21): 9829–9845. doi:10.18632/aging.102430. PMC   6874430 . PMID   31730540..
  19. ↑ Bürkle A, Grube K, Küpper JH (1992). "Poly(ADP-ribosyl)ation: its role in inducible DNA amplification, and its correlation with the longevity of mammalian species". Exp Clin Immunogenet. 9 (4): 230–40. PMID   1307244.
  20. ↑ Muiras ML, Müller M, Schächter F, Bürkle A (April 1998). "Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians". J Mol Med (Berl). 76 (5): 346–54. doi:10.1007/s001090050226. PMID   9587069.
  21. ↑ Zhu JL, Vestergaard M, Madsen KM, Olsen J (2008). "Paternal age and mortality in children". European Journal of Epidemiology. 23 (7): 443–7. doi:10.1007/s10654-008-9253-3. PMID   18437509. S2CID   2092996.
  22. ↑ "In this particular study, no adjustment was made for the health of the mother, and this could have had a large effect on child mortality." National Health Service (UK), "Older Dads and the Death of Children," (accessed 15 November 2013)
  23. ↑ Tournaye 2009, p. 102
  24. ↑ Eisenberg DT, Hayes MG, Kuzawa CW (June 2012). "Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants". Proceedings of the National Academy of Sciences of the United States of America. 109 (26): 10251–6. Bibcode:2012PNAS..10910251E. doi: 10.1073/pnas.1202092109 . PMC   3387085 . PMID   22689985.

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