| CSODM | Carboxyfullerene SOD mimetic | Administration of a small-molecule synthetic enzyme superoxide dismutase mimetic to wild-type (i.e. non-transgenic; non-senescence accelerated) mice starting at middle age significantly extends lifespan and reduces age-associated oxidative stress and mitochondrial radical production. Treatment also improves performance on Morris water maze learning and memory task and therefore rescues age-related cognitive impairment [17079053].
Carboxyfullerene SOD mimetic is an antioxidant with mitochondrial activity and nervous system penetration capability [17079053]. | — |
| Met | Metformin | In nematode metformin treatment extends healthspan, slows lipofuscin accumulation, extends mean lifespan and prolongs healthful locomotory ability in a dose-dependent manner as well as reduces fecundity. AMPK and its activating kinase LKB1 are essential for these health benefits. Oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin-confered healthspan too as it must be expressed in both neurons and intestines [20090912].
In fruit fly feeding metformin to adult results in robust AMPK activation and reduces lipid stores, but does not increase lifespan in either males or females. Administration of high concentration are even toxic [23077661].
Chronic treatment of female transgenic HER-2/neu mice with metformin slightly decreases food consumption but fails to reduce body weight or temperature, slows down age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolongs mean lifespan by 8% (p < 0.05), the mean lifespan of last 10% survivors by 13.1% and maximum lifespan by 1 month. Metformin treatment significantly decreases incidence and size of mammary adenocarcinomas and increases the mean latency of the tumors [16125352].
Chronic treatment of female outbred SHR mice with metformin slightly modified food consumption but decreases the body weight after the age of 20 months, slows down the age-related switch-off of estrous function, increases mean lifespan by 37.8% mean lifespan of the last 10% survivor by 20.8%, and maximum lifespan by 2.8 month (+10.3%). Treatment with metformin fails to influence blood estradiol concentration and spontaneous tumor incidence in female SHR mice [18728386].
In female SHR mice, metformin increases lifespan lifespan and postpones tumors when started at young and middle but not at old age.
Chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreases body temperature and postpones age-related switch-off of estrous function. Treatment with metformin started at the age of 3 months increases mean lifespan by 14% and maximum lifespan by 1 month. Treatment started at the age of 9 months insignificantly increases lifespan by only 6%, whereas the treatment started at the age of 15 months fails to increase lifespan. The mean lifespan of tumor-free mice increases by 21% (started at 3 months), by 7% (started at 9 months) and in contrast is reduced by 13% (started at 15 months). If started at 3 and 9 months, metformin delays the first tumors by 22% and 25%, correspondingly [21386129].
Transgenic FVB/N female mice carrying HER-2/neu mammary cancer gene receiving metformin with drinking water 5 days a week starting from the age of 2 months exhibit a slight reduced food consumption without change in water consumption and dynamics of weight gain. Their mean lifespan increases by 8% in 10% of the long-lived mice it is prolonged y 13.1% and the maximum lifespan is prolonged by 1 month. The total incidence of mammary adenocarcinoma and their multiplicity does not change under the effect of metformin, while the latency of tumor development increases and the mean diameter of tumors decreases [16224592].
Chronic treatment of inbred 129/Sv mice with metformin slightly modifies food consumption but fails to influence the dynamics of body weight, decreases by 13.4% the mean lifespan of make mice and slightly increases the mean lifespan of female mice (by 4.4%). Metformin treatment fails to influence tumor incidence in male 129/Sv mice, decreases by 3.5 times the incidence of malignant neoplasms in female mice while somehowwhat stimulate formation of benign vascualr tumors in the latter [21164223].
In rats metformine treatment reduces body weight significantly (despite similar food intake) but fails to significantly extend the lifespan at any quantile (25th, 50th, 75th, or 90th), overall or maximum lifespan (p > 0.05) [20304770]. | — |
| BHB | β-hydroxybutyrate | β-hydroxybutyrate (βOHB), ketone body is produced during a prolonged low-caloric or ketonic diet.
Low concentrations of βOHB helps protect cells from "oxidative stress". dietary restriction (DR) spurs βOHB production. βOHB is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Exogenous βOHB administration, fasting or DR increases global histone acetylation in mouse tissues. HDAC inhibition by βOHB is correlated with global changes in transcription, including oxidative stress factors Foxo3a and Mt2. Cells treated with βOHB have increased histone acetylation at Foxo3a and Mt2 promoters. Both Foxo3a and Mt2 are activated by selective depletion of HDAC1 and HDAC2. normally keeps a pair of genes, namely Foxo3a and Mt2 switched off [http://www.biocompare.com/Life-Science-News/126847-Gladstone-Scientists-Discover-Novel-Mechanism-By-Which-Calorie-Restriction-Influences-Longevity/; http://www.sciencemag.org/content/early/2012/12/05/science.1227166]. | — |
| — | 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]. | — |
| 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]. | — |
| DATS | Diallyl Trisulfide | DATS increases longevity apparently by enhancing skn-1.
Treatment with 5-10 μM DATS increases lifespan even when treatment is started during young adulthood. DATS increases the lifespan of daf-2 and daf-16 mutants, but not that of eat-2 mutants.
DATS treatment leads to the induction of the skn-1 target gene gst-4 and this induction is dependent on skn-1. DATS effect on lifespan is dependent on skn-1 activity in both intestine and ASI neurons [21296648]. | — |
| mtDNA | — | — | — |
| CYP2C gene family: CYP2C8, CYP2C9, CYP2C18, CYP2C19 | — | — | — |
| L-Theanine | L-Theanine | L-Theanine promotes paraquat resistance and extends lifespan of adult *C. elegans* [22422488]. | — |
| pka1 | cAMP-dependent protein kinase 1 | pka1 knockouts exhibits a three-fold increase in chronological lifespan with up to 187% longer maximum lifespan [16822282]. Deleting ser/thr cAMP-activated protein kinase pka1 extends chronological lifespan under normal condition, but there is no additive effect with DR [20075862]. | Fission yeast |
| sck2 | serine/threonine protein kinase Sck2 | Deletion of sck3 increases maximum chronological lifespan by 200%. Deletion mutant accumulated less reactive oxygen species and had delayed initiation of apoptosis. Additional deletion of pka1 further extend the lifespan of sck3 mutants [16822282]. | Fission yeast |
| wis1 | — | Constitutive active mutation of wis1 extends chronological lifespan and there is no further beneficial effect of DR [20075862]. | Fission yeast |
| atf1 | activating transcription factor 1 | Activation of transcription factor Atf1 by Sty1 is required for chronological lifespan extension and enhanced heat stress resistance by DR. Deleting atf1 cancels out DR-mediated chronological lifespan extension and enhanced heat stress resistance. Overexpressing atf1 is not sufficient to promote chronological lifespan extension in cells lacking sty1 [20075862]. | Fission yeast |
| sty1 | — | Deleting sty1 cancels out chronological lifespan extension and enhanced heat stress resistance by DR. Sty1 (phosphorylated) and Sty1-dependent gene transcription (atf1, gpx1, cta1, fbp1) is activated during DR in the stationary phase, but are barely activated in glucose rich medium [20075862]. | Fission yeast |
| gpa2 | Guanine nucleotide-binding protein alpha-2 subunit | gpa2 (alias git8) encodes the alpha subunit of a heterotrimeric G protein, which acts downstream of Git3. Git8 activity accelerates aging and inhibits the lifespan-extending effect of DR. Constitutive active mutation of gpa2 decreases chronological lifespan under AL (2% glucose) and almost completely cancels out the lifespan extending effect of DR (0.2% glucose) [19266076]. | Fission yeast |
| git3 | — | git3 encodes a G protein-coupled receptor for glucose. git3 deletion increases chronological lifespan in conditions where glucose consumption is not affected. Constitutive activation of the G-alpha subunit acting downstream of Git3 accelerates aging and inhibits the effect of DR. The anti-aging effect of DR and git3 deletion mutation is accompanied by increased respiration and lower ROS production [19266076]. | Fission yeast |
| AGP1 | high-Affinity Glutamine Permease 1 | Deletion of AGP1 extends chronological lifespan [16418483]. | Budding yeast |
| ATP2 | ATP synthase F1 subunit gamma | A temperature sensitive allele of ATP2 causes a clonal senescence phenotype resulting from the disruption of the age asymmetry between mother and daughter cells in that that daughter cells are born as old as they mother cells at 36 degree Celsius. This mutation of valine to isoleucine at amino acid 90 does not affect growth on non-fermentable carbon source. This allele is associated with loss of mitochondrial membrane potential as well as failure to segregate functional mitochondria to daughter cells [12242224]. | Budding yeast |
| BCY1 | Bypass of CYclase mutations | Disruption in BCY1 by mutation results decreases mean and maximum replicative lifespan by 37 and 16% and is associated with increased PKA activity [8195187]. | Budding yeast |
| BRE5 | BREfeldin A sensitivity 5 | Deletion of BRE5 increases mean replicative lifespan by 30% [16293764] and mean chronological lifespan in diploid cells [21447998] | Budding yeast |
| CCS1 | Copper Chaperone for SOD1 1 | Deletion of CCS1 reduces replicative lifespan by 50% [17460215]. | Budding yeast |
| CDC25 | Cell Division Cycle 25 | The CDC25-10 allele extends mean and maximum replicative lifespan by 34% and 18%, respectively, at 30 degree Celsius. cdc25-10 mutants have an extended replicative lifespan under AL. Growth on 0.5% glucose restriction does not further extend replicative lifespan of cdc25-10 mutants. CDC25 null mutant is not viable. CDC25 appears to act in the same genetic pathway as SIR2 and NPT1 and is suggested to be genetic model of DR [11000115]. | Budding yeast |
| CDC6 | Cell Division Cycle | The CDC6-1 conditional allele results in an approximately 20% increase in mean replicative life span. This allele is defective for replicative initiation form the rDNA ARS at 27 degree Celsius, resulting in a reduced rate of extrachromosomal rDNA circle accumulation [9428525]. The cdc6-1 allele results in genomic instability at the permissive temperature [8552037]. | Budding yeast |
| CLN3 | CycLiN 3 | Overexpression shortens chronological lifespan together with age-dependent increases in genome instability and apoptosis. While around 80% of wild-type cells are alive almost non CLN3 overexpressers are alive (under condition that avoids adaptive regrowth) [17710147]. | Budding yeast |
| CTT1 | CaTalase T 1 | Overexpression of cytosolic catalase T CTT1 alone slightly shortens stationary phase survival in strain DBY746. Overexpression CTT1 in combination with SOD1 increases stationary phase survival by about 10% [12586694]. Mutational inactivation [20696905] or deletion [21076178] of CTT1 lead to a longer chronological lifespan. | Budding yeast |
