| 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 |
| DDS | 4,4'-diaminodiphenylsulfone | In nematode treatment with DDS extends the lifespan [20974969].
DDS causes the delay of aging and decreases the level of a mitochondrial complex as well as lowers oxygen consumption and enhances oxidative stress resistance [20974969].
Pyruvate kinase is bound and inhibited by DDS in vitro and in vivo [20974969].
Hansen disease patients in Korea, who usually have taken DDS for several decades, have a longer lifespan in spite of their socioeconomic disadvantages [19084552]. | House mouse |
| Fgf21 | Fibroblast growth factor-21 | Overproduction of Fgf-21 increases mean lifespan of males by 30% and that of females by 39% [23066506].
Mice overproducing Fgf21 are lean throughout their lives and remain lean even while eating slightly more than wild-type mice. Fgf21 overproducers tend to be smaller than wild-type mice and female mice were infertile. Although Fgf21 overproducers have significantly lower bone density than wild-type, Fgf21-abundant mice exhibit no ill effects from the reduced bone density and remain active into old age without any broken bones.
Fgf21 seems to provide its health benefits by increasing insulin sensitivity and blocking the growth hormone/insulin-like growth factor-1 signaling.
Fgf21 acts as a hormone, is secreted by the liver during fasting and helps the body to adapt to starvation.
| House mouse |
| Lep | leptin | Lep knockout results in ob/ob mice which eats excessively and becomes profoundly obese. ob/ob mice live shorter on ad libitum, but achieve a lifespan similiar to control levels under DR, yet their precentage of body fat is much greater that that of controls [6608731]. | House mouse |
| Acacb | acetyl-Coenzyme A carboxylase beta | Acacb-null animals (alias Acc2-/-) exhibit upon regular diet an increase triglyceride breakdown, leaner phenotype, increased insulin sensitivity and no effect on lifespan [17923673]. | House mouse |
| MIR20A | microRNA 20a | Overexpression of MiR-20a in mouse embryonic fibroblasts induces senescence by lowering Lrf (a transcriptional repressor of the Mdm2 inhibitor p19ARF [15662416; 9529248]) protein levels and in turn increasing p19ARF levels [18596985]. | 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 |
| Terc | telomerase RNA component | Telomerase null mice exhibit age-dependent telomere shortening and shortened lifespan with succeeding generations. Median lifespan is reduced by 26% in G6 Terc(-/-) mice compared to wild-type or G1-G3 Terc(-/-) (18 months vs. 24 months). G6 Tec(-/-) display hair greying, hair loss, and ulcerative skin lesions, as well as impaired response to wound healing and hematoitopitic ablation, and an increased incidence of cancer [10089885]. Cells from Terc(-/-) mice (G4 and upward) exhibit chromosomes lacking detectable teloemre repeats, aneuplody, and end-to-end fusions [9335332]. | House mouse |
| Sod2 | superoxide dismutase 2, mitochondrial | Sod2(-/-) mice are born smaller, pale and less vigorous, and die with 7-10 days. The major problems are dilated cardiomyopathy, accumulaiton of lipid in various tissues particularly liver and skeletal muscle, and metabolic acidosis [7493016]. In another strain background Sod2(-/-) mice have severe anemia, degeneration of neurons in the basal ganglia and brainstem, and progressive weakness, fatigue, and cricling behavior [8790408]. Treatment of Sod(-/-) mice with superoxide dismuate/catalase mimetics (EUK-8, EUK-134, or EUK-189) partially rescues the short lifespan (mean lifespan 14-28 days) and other phenotypes [9462746].
Two-fold overexpression of Sod2 in young (4-6 months) and old (26-28 months) throughout the life results in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production, without any change on lifespan or age-related pathology [19633237].
Life-long reduction in MnSOD activity leads to increased levels of oxidative DNA damage and increase cancer incidience, but does not appear to affect aging. Sod2(+/-) mice that have a 50% reduction in MnSOD activity in all tissues throughout the life have increased oxidative damage as evidenced by significantly elevated levels of 8-oxo-2-deoxyguanosine in nuclear DNA (in all tissues) as well as in mitochondrial DNA (in lver and brain). Increased oxidative damage to DNA is associated with a 100% increase in tumor incidience in old Sod2(+/-) mice. However, mean and maximum lifespan of Sod2(+/-) and wild-type mice is identical. Biomarkers of aging, such as cataract formation, immune response, and formation of glycooxidation products carboxylmethyl lysine and pentosidine in skin collagen changes with age to the same extent in both wild-type and Sod2(+/-) mice.
Sod2(+/-);Gpx(-/-) animals exhibit no reduction in lifespan, despite increased levels of oxidative damage and neoplasms as well as tumorgenesis [19776219]. | House mouse |
| Rgn | regucalcin | Survival among make animals lacking Rgn (alias SMP30) is 50% at 180 days compared to 100% among controls [N. Maruyama, unpublished data].
SMP30-/- mutant mice are indstuguishibale form their SMP30+/+ littermates in terms of development and fertilization capacity [12368201]. However, -/- mice were more susceptible to liver injury after treatment with anti-FAS antibody. SMP30-/- hepatocytes cultures in vitro are more susceptible to apoptosis induced by tumor-necrosis factor (TNF-alpha) plus actinomycin D (ActD) than SMP30+/+ hepatocytes.
| House mouse |
| Hells | helicase, lymphoid specific | A hypomorphic deletion of helicase domains 3, 4 and part of 2, leads to expression of a C-terminal truncated Hells protein causing an extremely short lifespan. with 60% of homozyogous mutants dying after birth and remaining 40% surviving up to seven weeks (around 25 days) [15105378].
Hells disruption results in genomic hypomethylation, de-repression of silenced genes, and premature aging, characterized by decreased proliferation, increased replicative senescence, and altered expression of Bmi-1 and p16INK4a. Hells mutant exhibit significant hypoglycemia, low birth weight and growth retardation, and signs of premature aging such as greying hair and balding, reduced fat deposition, unstable gait, cachexia, and kyphosis [15105378]. | House mouse |
| Dgat1 | Diacylglycerol O-acyltransferase 1 | Deficiency in Dagat1 promotes leanless and extends mean, median and oldest 10% survival by 23, 26 and 9% without limiting food intake [22291164]. | House mouse |
| Gh | growth hormone 1 | Overexpression of a growth hormone antagonist (a mutated growth hormone that competes with the endogenous one) in mice has no effect on lifespan [12933651]. | House mouse |
| Prkar2b | protein kinase, cAMP dependent regulatory, type II beta | Loss of function of Prkar2b results in mice that are lean and insulin sensitive. Both median and maximum lifespan is increased by 14%. Median lifespan is increasesd (from 884 to 1005) and 80% lifespan increased from 941 to 1073 days. There is no difference either in median or 80% lifespan in female genotypes [19536287]. | 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 |
| — | Rapamycin | Rapamcyin increases mouse lifespan even when administrated late in life [19587680]. | 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 |
| Pten | phosphatase and tensin homolog | Increasing gene dosage via homogeneous and moderate overexpression, while retaining its normal pattern of tissue expression of Pten increases mean, median and maximum lifespan in both females and males. Mean lifespan is extended by 18% (males), 11% (females) and 14% (both). Median lifespan in males, females and both increases by 12%, 16% and 12%, respectively [22405073]. Transgenic Pten mice carrying the additional genomic copies of Pten are protected from cancer and present a significant extension of lifespan that is independent of their lower cancer incidence. Pten(g) mice have an increased energy expenditure and protection from metabolic pathologies [22405073].
PTEN promotes oxidative phosphorylation and decreases glycolysis. PTEN aslo upregulates UCP1 expression in brown adipocytes, which enhances their nutrient burning capacity and decreases adiposity and associated pathologies [23245767]
| House mouse |
| Sirt6 | sirtuin 6 (silent mating type information regulation 2, homolog) 6 (S. cerevisiae) | Sirt6 knockout mice develop signs of premature ageing including a short lifespan [16439206].
Overexpression of Sirt6 in male mice lengthens the median lifespan by 9.9-14.5% and maximum lifespan by 13.1-15.8% [22367546].
Mice without Sirt6 have a higher risk of gastrointestinal cancers. SIRT6 dampens cancer growth by repressing aerobic glycolysis (i.e. conversion of glucose to lactate; a major feature of cancer cells). Loss of Sirt6 increases the number, size and aggressiveness of tumors. Sirt6 loss leads to tumor formation even without activation of oncogenes. Transformed SIRT6-deficient cells exhibit increased glycolysis and tumor growth. Sirt6 inhibits the transcriptional activity of the oncogene Myc via corepression [23217706]. Sirt6 also protects against diet-induced obesity [http://www.biocompare.com/Life-Science-News/127206-Anti-Aging-Gene-Identified-As-Tumor-Suppressor-In-Mice-Research-Finds/].
| House mouse |
| Nfkbia | nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha | Overexpression of an endothelial dominant-negatvie I?B? gene prolonged the lifespan [22302838]. | House mouse |
| Gsta4 | glutathione S-transferase, alpha 4 | Gsta4 null mice, had impaired 4-hydroxynonenal detoxification, but extended average lifespan. | House mouse |
| Cisd2 | CDGSH iron sulfur domain 2 | Cisd2 knockouts expire premature ageing and reduced lifespan [19451219]. A persistent level of Cisd2 achieved by transgenic expression extends mean, median and maximum lifespan without any apparent deleterious side effects [22661501]. | House mouse |
| Zmpste24 | zinc metallopeptidase, STE24 homolog (S. cerevisiae) | Knockout mice exhibit nuclear architecture abnormalities and signs of accelerated ageing. | House mouse |
