| CCL2 | chemokine (C-C motif) ligand 2 | CCL2 levels in plasma increase with age and it is part of the senescence-associated secretory phenotype [19648977]. | Human |
| Chek2 | CHK2 checkpoint homolog (S. pombe) | Mice hypomorphic for Brca1 and double mutant for chk2 exhibit signs of premature ageing. | House mouse |
| cul-1 | CULlin 1 | RNAi of cul-1 decreases lifespan of daf-2 mutant, but not of wild-type or glp-1 mutant. The CUL-1 complex functions in postmitotic, adult somatic tissues of insulin/insulin-like growth factor-1-signaling mutants to enhance longevity. It may act, at least in part, by promoting the transcriptional activity of DAF-16/FOXO [17392428]. | Nematode |
| cit-1.2 | CyclIn T 1.2 | RNA interference cit-1.2 decreases median lifespan by 27% in daf-2 mutants [18006689]. | Nematode |
| 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 |
| 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 |
| dcp-66 | Deacetylase Complex Protein 66 | dcp-66 RNAi shortens the mean lifespan by 29% and suppresses lifespan extension by isp-1 mutation, but does not significantly affect lifespan extension neither by eat-2 nor daf-2 mutation [22829775]. | Nematode |
| ELOVL2 | elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 2 | In breast, kidney and lung tissues the makers cg23606718 and cg16867657 were commonly differentially methylated with age and both have been annotated to ELOVL2 [23177740], which is linked to photoaging response in human skin [20514327]. | Human |
| Chromosome 4 | epithelial cell adhesion molecule | — | Human |
| 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 |
| 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 |
| Ercc4 | Excision repair cross-complementing rodent repair deficiency, complementation group 4 | ERCC4-ERCC1-deficient mice exhibit signs of premature aging [17183314]. | House mouse |
| EXO1 | exonuclease 1 | The rs1776180 C allele in the promoter of EXO1 is significantly enriched in female Germans centenarians and this can be replicated in 445 female French centenarians. The C allele leads to the loss of binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression [19698732].EXO1 was found to be associated with longevity [19698732]. EXO1 was not found to be associated with longevity [23770741]. | Human |
| FAR3 | Factor ARrest 3 | Deletion of FAR3 significantly reduces mean chronological lifespan under starvation/extreme DR relatively to wild-type [20657825]. | Budding yeast |
| FAR11 | Factor ARrest 3 | Deletion of FAR11 significantly reduces mean chronological lifespan under starvation/extreme DR relatively to wild-type [20657825]. | Budding yeast |
| FCY1 | FluoroCYtosine resistance 1 | Deletion of FCY1 does non-significantly decrease mean and maximum replicative lifespan by 4% and 8%, respectively [20550517]. | Budding yeast |
| 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 |
| — | Germline | Sterilization prolongs lifespan, in species from insect to humans.
In hermaphrodite C. elegans, removing sperm and egg-producing cells extends lifespan by 50%. Removing those cells triggers a reaction in the surrounding tissue. The signal is send out in the form of a steroid hormone, that turns on a molecular switch, which switches them into a kind of survival mode. Specifically, remaining gonadal cells trigger production of a steroid hormone dafachronic acid. Dafachronic acid activates miRNAs, which work as tiny molecular switch causing changes in gene expression that promote longevity. The same steroid hormone-miRNA switch is part of the developmental clock. The loss of the germ cells ultimately causes the worm to use developmental timers to put in motion a lifespan-prolonging programme [23239738]. | — |
| GH1 | Growth hormone 1 | Transgenic mice overexpressing bovine GH1 are bigger than controls and display early onset of pathological changes in the kidneys such glomerulosis and glomerulonephritis as well as signs of premature aging such as a shortened lifespan, increased astrogliosis, shortened reproductive lifepsan and early onset of age-related changes in cognitive function, hypothalamic neurotransmitter turnover, and plasma corticosterone levels [14583653]. | Cattle |
| GHR | growth hormone receptor | Individuals with low GH/IGF-I signaling due to a defect in the growth hormone receptor (GHR) are protected against cancer. Among the human individuals with a defect in GHR no cancer deaths were observed. GHR deficiency does not appear to extend lifespan because it is associated with increased risk of heart disease [21325617]. Variants in GHR were found to be associated with longevity [19489743]. | Human |
| GTPBP10 | GTP-binding protein 10 (putative) | Age-related differential methylation of the genetic marker rs42663, which is missense mutation in GTPBP10 is statistically significant association with age and aging rate. GTPB10 associates with cg27367526 in STEAP2 [23177740]. | Human |
| HCFC1 | host cell factor C1 (VP16-accessory protein) | HCFC1 is a cronserved protein with a predominant nuclear localisation [7876203]. The mammalian HCF-1 is involved in cell cycle progression, both at the G1/S transition and at M phase and cytokinesis [12743030 ;15200950;17612494]. It acts by binding to and regulating many different transcripts and chromatin factors and assembling appropriate protein complexes for context-dependent gene expression regulation. HCF-1 helps to recruit the activating Set1/Ash2 histone methyltransferase complex [18043729]. Mammalian HCF-1 recruits te Set1/Ash2 histone methyltransferase activating complex to E2F1 and the Sin3 histone deacetylase repressive complex to E2F4 at the appropriate time of the cell cycle, which is likely to reinforce the activating or repressive functions of the respective E2F family members [17612494]. | Human |
| kri-1 | human KRIT 1 (Krev interaction trapped/cerebral cavernous malformation 1) homolog | RNA interference suppresses glp-1 life-extension but does not shorten lifespan of wildtype strains. kri-1(ok1251) mutation does not shorten the lifespan significantly [22560223]. | Nematode |
| H2S | Hydrogen Sulfide | Hydrogen sulfide (H2S) is a colorless, poisonousness, flammable gas with the characteristic foul odor of rotten eggs. A few breath of air containing high levels H2S can cause death, while lower long-term exposure can cause eye irritation, headache, and fatigue.
The human body produces small amounts of hydrogen sulfide and uses it as signaling molecule. It has a variety of physiological effects. For instance, it relaxes the vascular endothelium and smooth muscle cells, which is important to maintaining clean arteries as one ages. It is an important signaling molecule because of its significant effects on the cardiovascular and nervous systems.
Hydrogen sulfide appears to slow aging by inhibiting free-radical reactions via the activation of SIRT1 and probably through its Interactions with Klotho.
Klotho seems to be upregulated by hydrogen sulfide and extends lifespan via a number of different pathways, some of which promote production of endogenous antioxidants.
H2S produced in the kidneys has direct angiotension-converting enzyme (ACE) inhibiting activity. It is therefore an ACE inhibitor, just like certain drugs that mitigate high blood pressure.
Plasma hydrogen sulfide declines with age and is lower in spontaneously hypertensive rats. A lack of hydrogen peroxide is in general implicated in cardiovascular disease. Declining hydrogen sulfide levels also underline neurological health. Endogenous hydrogen sulfide is lower in animal model of Parkinson disease and depressed in the brains of patients with Alzheimer's disease. Hydrogen sulfide may also protective in animal models as well as humans against cancer [23297346]. | — |
| IMD2 | IMP Dehydrogenase 2 | Deletion of IMD2 does non-significantly decrease mean replicative lifespan by 1% and non-significantly increased maximum replicative lifespan by 21% [20550517]. | Budding yeast |
