Factors

We need to know every factor which determines lifespan.

Lifespan factors often but not always originate from defined genetic elements. They are not just genes, by definition they can be anything for which a Classifications schema can be build for that is related to the regulation of lifespan, such entities may include Single-Nucleotide Polymorphism, transcript variants, proteins and their complexes, compounds (i.e. small molecules like metabolites and drugs), etc. A factor should be based on a defined molecular entity or genomic position and been classified. It shall be highly flexible and scalable Concept.

While individual lifespan factors within each species or precise defined molecular entities will be captured within the Lifespan App, Data Entries of the Data App may summarize for instance the relevance of each factor class (e.g. homologous group; chemical derivate of related structure and properties, etc.) as well as draw overall conclusions. o

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  • symbol name observation species
    Mir669c microRNA 669c Expression increases with age in mouse liver. The miRNA downregulates detoxification and regeneration genes, which may contribute to aging [18561983]. House mouse
    miR-214 microRNA 214 Expression increases with age in mouse liver. The miRNA downregulates detoxification and regeneration genes, which may contribute to aging [18561983]. House mouse
    Mir27a MicroRNA 27a In Ames dwarf mice (which displays delayed Aging), Mir27a expression is significantly higher than in control mice. Mir27a may be responsible for delayed Aging in dwarf mice: it suppresses the expression of ODC1 and SRM, which in turn suppresses polyamine synthesis in dwarf mice liver. Part of the ability of dwarf mice to suppress or avoid tumor or Cancer growth may be attributed to the decreased Polyamine biosynthesis. [19878148] House mouse
    CCL2 chemokine (C-C motif) ligand 2 CCL2 levels are evaluated in old unpaired and young heterochronic (with old animals) paired mice [21886162]. House mouse
    CCL11 chemokine (C-C motif) ligand 11 CCL11 is an age-related systemic factor associated with decreased neurogenesis. Relative levels of CCL11 increase in the plasma during aging an in young mice during Heterochronic Parabiosis [21886162]. House mouse
    Lamp2a lysosomal-associated membrane protein 2 Lamp2a, the receptor for chaperone-mediate autophagy (CMA) decreases in abundance with age. Maintaining the amount of the Lamp2a (in a double transgenic mice) specifically in the liver at levels found in young adults prevents age-dependent decrease in receptor abundance at the cellular and organ levels. In this mice CMA activity is maintained until advanced ages which results in preservation of the autophagic activity and is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function [19115216; 18690243]. Lamp2a expression restored not only CMA but also macrophagy and proteasomal degradation to the level observed in young liver as well as `youthful` mitochondrial function and cellular ATP abundance and overall youthful liver functions [18776878]. House mouse
    Ucp3 uncoupling protein 3 (mitochondrial, proton carrier) Metabolic intensity (daily food energy/body mass) correlates with longevity in MF1 mice. The animals with the highest quartile of metabolic intensities have a mean lifespan of 36% longer than animals with the lowest quartile of metabolic intensities. The highest metabolism of long-lived animals can be attributed to increased uncoupling Ucp3 [15153176]. Skeletal muscle mitochondria isolated from high metabolism mice are more uncoupled that those from low metabolism mice [15153176]. House mouse
    HNRNPD eterogeneous nuclear ribonucleoprotein D (AU-rich element RNA binding protein 1, 37kDa) HNRNPD controls inflammation by turning off the inflammatory response to stop the onset of septic shock. Cessation of inflammatory cytokine respisne is mediated partly through cytokine mRNA degradation facilitated by RNA-binding proteins, including HNRNPD. HNRNPD deletion leads to accelerated aging as evidenced by strinking telomere erosion, markedly increased DNA damage repsosne at telomere ends, pronounced cellular senescence and rapid premature aging that increases with successive generations. HNRNPD which is a family of four related genes also maintains the integrity of chromosomes by activating telomerase, because HNRNPD strongly activates the transcription promoter for Tert [Pont et al., 2012]. House mouse
    Foxo3 House mouse
    Sirt1 sirtuin 1 (silent mating type information regulation 2, homolog) 1 (S. cerevisiae) Whole-body deletion of Sirt1 in the adulthood results in mice which are seemingly normal in every way. When mice were given low doses of resveratrol after Sirt1 was disabled, there were no discernible improvement in mitochondrial function or any parameter, while mice with normal Sirt1 function given reservatrol showed dramatic increases in energy, mitochondrial biogenesis and function, AMPK activation and increased NAD+ levels in skeletal muscle. When mice lacking Sirt1 were given low doses of reserveratrol, AMPK was unaffected. When doses were significantly increased in these mice, AMPK was activated in a SIRT1-indepent manner, but still no benefit to mitochondrial function resulted [22560220]. Sirt1 overexpression mimicks the effect on reservatrol on mitochondrial function, but failed to extend lifespan [22560220]. SIRT1 knock-out mouse embryonic fibroblasts (MEFs) have a significant greater replicative capacity in culture. p19ARF levels are significantly reduced in SIRT1 knock-out MEFs [16054100]. Sirt1-null mice do not exhibit lifespan extension upon Dietary Restriction [18335035]. Sirt1 is required for high-magnitude circadian transcription of several core clock genes. It deacetylates Per2, Arntl and histones of clock-controlled genes [18662546]. SIRT1 directly [21187328] and indirectly [20450879] prevents telomere shortening. House mouse
    Cdkn2a cyclin-dependent kinase inhibitor 2A Cdkn2a encodes different transcripts involved mostly in cell cycle regulation and cellular senescence [12882406], but it can also act as a tumor suppressor. Its expression level increase with age in rodents [15520862]. super-Ink4a/Arf mice carrying a transgenic copy of a large genomic segment containing an intact and complete copy of the Cdkn2a (a.k.a. Ink4a/Arf) gene are significantly protected from cancer and had no indication of accelerated aging. Cells derived from super-Ink4a/Arf mice have increased resistance to in vitro immortalization and oncogenic transformation [15520276]. Loss of Cdkn2a in mice results in tumour susceptibility [11544530]. Mice deficient in Cdkn2a have smaller age-related decline in self-renewal potential as this process is associated with increasing levels of Cdkn2a [16957738]. Increased levels of p16 are associated with aging (Krishnamurthy et al., 2006; Molofsky et al., 2006) and a bona fide marker of cellular senescence (Collado et al., 2007). p16INK4a accumulates in many tissues as a function of advancing age (Krishnamurthy et al., 2004; Nielsen et al., 1999; Zindy et al., 1997) and is an effector of senescence (Campisi, 2003; Park et al., 2004), p16INK4a is a potent inhibitor of proliferative kinase Cdk4 (Lowe and Sherr, 2003) which is essential for pancreatic ?-cell proliferation in adult mammals (Rane et al., 1999; Tsutsui et al., 1999). p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas and islet-specific expression of p16INK4a increases markedly with aging (Krishnamurthy et al., 2006). Aging in mammals is associated with reduced regenerative capacity in tissues that contain stem cells (Chien and Karsenty, 2005) which is probably partially caused by senescence of progenitors with age (Campisi, 2005; Lombard et al., 2005). Progenitor proliferation in subventricular zone and neurogenesis in the olfactory bulb as well as multipotent progenitor frequency and self-renewal potential, all decline with ageing the mouse forebrain. The decline in progenitor frequency and function correlate with increased expression of p16INK4a (Molofsky et al., 2006). Aging p16INK4a-deficient mice exhibit a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis and the frequency and self-renewal potential of multipotent progenitors (Molofsky et al., 2006). p16 expression in skin cells is significantly lower the the group that has a strong family history of longevity. As such a younger biological age associates with lower levels of p16INKfa positive cells [22612594]. p16 expression increases exponentially with age. Expression of p16INK4a with age does not predict cancer development. p16INK4a activation is a characteristic of all emerging cancers [http://denigma.de/url/3n]. House mouse
    Rae1 RAE1 RNA export 1 homolog (S. pombe) Haploinsufficiency of Bub3 and Rae1, but not haploinsufficiency of either gene by itself, reduces lifespan by 12% and appears to accelerate ageing. House mouse
    Nos3 nitric oxide synthase 3, endothelial cell Knockout males exhibited premature death and age-related cardiac dysfunction but not females. House mouse
    Neil1 nei endonuclease VIII-like 1 (E. coli) Knockout mice develop severe obesity, dyslipidemia, fatty liver disease, increased levels of DNA damage in the mtDNA, and have a tendency to develop hyperinsulinemia. House mouse
    Mgat5 mannoside acetylglucosaminyltransferase 5 Although grossly normal at birth, knockout mice display multiple deficiencies with age including hypersensitivity to autoimmune disease, higher oxidative metabolism, resistance to weight-gain, and signs of early ageing such as osteoporosis, decreased muscle mass, and depletion of adult stem cells. Interestingly, Mgat5-/-Pten+/- and Mgat5+/-Pten+/- mutant mice showed a small but significant increase in lifespan when compared to Pten+/- mice, accompanied by an apparent delay in the inevitable development of cancer in Pten+/- mice. House mouse
    Foxm1 Forkhead box M1 Deletion of Foxm1 causes age-related deterioration in liver regeneration. Increased hepatocyte expression in 12-month-old (aged) transgenic mice of Foxm1b alone is sufficient to restore hepatocyte proliferation to levels found in 2-month-old (young) regenerating liver [14647066]. House mouse
    Ercc4 Excision repair cross-complementing rodent repair deficiency, complementation group 4 ERCC4-ERCC1-deficient mice exhibit signs of premature aging [17183314]. House mouse
    Ercc2 Excision repair cross-complementing rodent repair deficiency, complementation group 2 Mutations in Ercc2 increases cancer incidence and appear to accelerate ageing. Homozyogus mutation of Ercc2 results in an extreme shortening (71%) of lifespan (mean lifespan = 7 months) relative to wild-type (mean lifespan = 24 months) [de Boer et al. 2002]. The shortened lifespan of the mutant mouse is accompanied by symptoms of premature aging including osteoporosis, early greying, cahexia, and infertility. It provides a mouse model for the britte hair disorder trichothiodystrophy (TTD) as it phenotypes include britte hair, UV sensitivity, and developmental defects [9651581]. House mouse
    Chek2 CHK2 checkpoint homolog (S. pombe) Mice hypomorphic for Brca1 and double mutant for chk2 exhibit signs of premature ageing. House mouse
    Cdkn1a Cyclin-dependent kinase inhibitor 1A Deletion of Cdkna1 (alias p21) prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres and improves the repopulation capacity and self-renewal of hematopoietic stem cells [17143283]. The p21(-/-) strains like the Cdkn1a(tmi/Tyj) exhibits enormous regenerative capacities as it closes ear holes similar to MRL mice [20231440; 21722344]. House mouse
    Bub3 budding uninhibited by benzimidazoles 3 homolog (S. cerevisiae) Haploinsufficiency of Bub3 and Rae1, but not haploinsufficiency of either gene by itself, reduces lifespan by 12% and appears to accelerate aging [16476774]. House mouse
    bax Bcl2-associated X protein Inactivation of proapoptotic Bax extends fertile potential and minimized age-related health problems, including bone and muscle loss, excess fat deposition, alopecia, cataracts, deafness, increased anxiety, and selective attention deficit. Bax deficiency does not lead to an increase in tumor incidence. Despite the apparently increased quality of life of aging females lacing Bax, there is no significant differences in overall lifespan [17360389]. House mouse
    Atm Ataxia telangiectasia mutated homolog (human) Atm-deficient mice are viable, retarded in growth, infertile (male produce no mature sperm and female no gametes), display neurological dysfunction, and exhibit severe defects in T cell maturation while going on to develop thymomas [8917548; 8689683]. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age [8843194]. Cells of Atm(-/-) mice exhibit slow growth also in culture and premature senescence, telomeres are extensively shortened in multiple tissues [8689683]. Mice mutant for Atm and Terc display progressive multi-organ system compromise and features of accelerated aging [12540856]. House mouse
    Arntl aryl hydrocarbon receptor nuclear translocator-like Arntl knockout mice display symptoms of premature aging including a shorter lifespan, sarcopenia, cataracts, less subcutaneous fat, and organ shrinkage [16847346]. House mouse
    • 24 factors
    Factors are an extension of GenAge and GenDR.

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