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Longevity (as it applies to supplementation) is the concept of promoting or preserving youth and vitality via delaying the inherent human aging process. Research into this topic is young and speculative, but generally centers around autophagy.

Our evidence-based analysis on longevity features 164 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
Last Updated:

Research Breakdown on Longevity

1Molecular Targets/Pathways of Interest

Various metabolic pathways are considered locus points for longevity, either in an enhancing or attenuating manner. These pathways highly influence on another, and are likely druggable targets to promote longevity
A large amount of research is conducted in nematodes (C. Elegans) with some more research conducted in mice and rats. Research in humans is somewhat nonexistent due to practical complications with monitoring a study for an entire lifespan


Telomerase is a ribonucleoprotein that mediates telomere length (telomeres being 'caps' on chromosomes), which appear to decline in length with age.[1][2] Telomerase is composed of two subunits, the catalytic TERT subunit (also known as TRT or Est2) which forms the core of the enzyme integral telomerase RNA (sometimes referred to as TR, TER, TERC, or TLC1) that provides the template for TERT;[3][4] the catalytic cycle involves the synthesis of a single telomere repeat at the 3′ end of the telomeric DNA primer and the regeneration of the template for the synthesis of additional repeats.[4] There are other proteins associated with telomerase (known as accessory proteins) that are not outright required for its function.[5][6][7]

Telomeres are investigated into longevity due to their correlation with aging, but have been demonstrated to be independent of aging in C. Elegans[8] and nutraceutical interventions with Astragaloside IV (from astragalus membranaceus) have successfully increased telomere length in aged rats independent of longevity promotion.[9]

Telomeres are commonly associated with aging, but may be a biomarker of aging rather than a druggable target. Increasing activity of telomerase or preserving telomere length via exogenous agents does not necessary promote longevity, although telomerase cannot be ruled out as a druggable target either


Human FOXO (ortholog of DAF-16 in C. Elegans) is a term used to refer to a group of genes known as FKHRL1 (FOXO3a),[10] FKHR (FOXO1), and AFX (FOXO4);[11][12] DAF-16 and FOXO are commonly used interchangeably,[11] and refer to the main nuclear mechanisms that result from IIS and TOR signalling, both of those pathways (commonly seen as anti-longevity) promote nuclear exclusion of FOXO and reduce its expression of gene products.

FOXO is activated by reactive oxygen species (ROS) and appears to be a negative REDOX regulator via its gene products,[13][14] and is positively modulated by AMPK (molecular target of metformin and berberine, also positively regulated by ROS[15][16])

When DAF-16/FOXO is able to signal via the genome (with its coregulator Smk-1[17]), the gene products are associated with dauer formation and the stress response as well as life extension. Gene products that are increased following nuclear accumulation of DAF-16 (and thus are implicated in longevity promotion) include heat shock proteins (HSP-70 and HSP16-1[18]), the SIR-2 family of genes,[18] increased PGC-1a activity[19] and superoxide dismutase 3 (SOD3).[18][20] Other genes found to be upregulated via DAF-16 include vha-3, E3 ubiquitin ligase, zfp-1, and sarcoendoplasmic reticulum calcium ATPase (not conclusive list).[21]

Nuclear accumulation of DAF-16 appears to induce gene products with a wide range of attributes but mostly related to stress survival and oxidant defense, with a notable increase in superoxide dismutase. There may be significant interplay between activation of DAF-16 and chaperone-mediated autophagy


PHA-4 is the C. Elegans ortholog to the human FOXA family of genes,[22][23] which consists of FOXA1-3 and appears to be mandatory for the benefit of caloric restriction on longevity.[24] PHA4 is additionally mandatory for the development of the C.Elegans pharynx that mediates feeding[25] and influences the genome (response elements here[26]) to induce the gene products. FOXA is also activated by hepatocyte nuclear factors (HFNs) with HFNα, β, and γ corresponding to FOXA1, FOXA2, and FOXA3 respectively.

FOXA1 appears to be regulated by steroid hormones, as FOXA1 appears to be mandatory for androgen receptor signalling as a cofactor[27][28] and is highly involved in the genomic signalling of estrogen (α subset)[29] insofar that it is mandatory for development of breast tissue.[30]

FOXA2 is additionally activated by both glucocorticoids and cAMP,[31] both increased during fasting. FOXA2 is also known to interact with bile acids[32] which may explain the synergism between caloric restriction and supplemental lithocholic acid.

FOXA signalling appears to be mandatory for the benefits of caloric restriction on lifespan, although FOXA promoters are quite general and interact with a variety of hormones (including both steroid hormone classes of androgens and estrogens)

1.4Insulin/DAF-2/IGF-1 signalling pathway

The Insulin/IGF-1 signalling pathway (IIS; C. Elegans ortholog of the receptor is Daf-2) appears to be a regulator of longevity in various research models[33][34][35][36] and ultimaltely works via FOXO/DAF-16.[12][37][38] Phosphorylation of DAF-16 by Akt (downstream of the insulin receptor and upstream of TOR) accumulates DAF-16 in the cytoplasm[39][37][10] which prevents nuclear signalling and life promoting effects, which require nuclear accumulation (occurs when not phosphorylated[37]). Activation of this pathway tends to reduce longevity, as mutants (with subactive levels of signalling) have prolonged vitality and life span.[40][24]

Akt also activates TOR signalling (via the substrate PRAS40[41]) and is able to phosphorylate TSC1, inactivating it and preserving mTOR activation via Rheb.[42][43] These mechanisms establish Akt as a positive modulator of TOR, and the IIS pathway with the TOR pathway (next section) are intimately linked.

Signalling through the insulin receptor can activate Akt and promotes cytoplasmic accumulation and nuclear restriction of FOXO/Daf-16. Signalling via the insulin receptor is likely one of the more biologically relevant mechanisms underlying anti-longevity

Prolonged signalling via the insulin receptor towards FOXO/DAF-16 appears to upregulate components of the Akt pathway as negative feedback.[13]

Some negative feedback potential of FOXO on the IIS may reduce the anti-longevity effects of this pathway in practical situations

1.5Target of Rapamycin (TOR)

TOR is a protein that was identified as the target of the immunosuppresive drug Rapamycin (Sirolimus), and is called mTOR or CeTOR depending on if the protein is mammalian (mTOR) or from C. Elegans (CeTOR). TOR modulates ribosome biogenesis, autophagy and transcription[44] and is a molecular target of leucine and the metabolite HMB.

TOR has a complex known as complex 1 (or TORC1), which is considered to be of more interest as the other complex (TORC2) is insensitive to Rapamycin; components of this complex include TOR kinase (let-363 in C. Elegans),[45] Raptor (daf-15 in C. Elegans),[46] and LST8[47] although LST8 does not appear vital to TORc1 signalling.[48] LST8 is also involved in complex 2 and is the only subset present in both complexes,[48] and complex 2 also includes Rictor (Rapamycin Insensitive Companion of TOR), Sin1 (stress-activated map kinase-interacting protein 1), and TOR itself.[49][50]

TOR (mTOR in mammals) is a pathway intermediate in the IIS that is also a direct target of various metabolites, and is considered a druggable target due to its inhibition by rapamycin promoting longevity

TOR partially antagonizes PHA-4/FOXA signalling[47] secondary to the PHA-4 suppressor known as ruvb-1[51] and as such can reduce the longevity effects of caloric restriction.

The small GTPase protein known as Rheb appears to directly stimulate TORC1[52][53][54] and is the intermediate by which the tumor suppressor proteins TSC1 and TSC2 inhibit TORc1, as the sequestering of Rheb by TSCs reduces activation of TORc1.[55][56] Rag GTPases are also implicated in positively regulating TORC1[57] via the raptor subset[58] and is inhibited by Metformin.[59]

TOR is activated in periods of nutrient excess and by signalling molecules induced by nutrient excess, such as amino acids; activation of the TOR pathway is known to suppress the FOXA pathway, which is mandatory for caloric-restriction related benefits to longevity

1.6Cannabinoid Signalling

Cannabinoids are endogenous fatty acid amides that signal through cannabinoid receptors, known as CB1 and CB2; these receptors are named after cannabis (Marijuana) where they were first characterized, and endogenous cannabinoids include anandamide and oleamide.

At least one study has note that abolishing the CB1 receptor has promoted longevity (C. Elegans) while either reducing N-acylethanolamine concentrations or increasing the activity of the FAAH enzyme (which metabolizes N-acylethanolamines) was able to promote lifespan[60] although elsewhere CB1 knockout mice have shortened lifespans.[61]

Signalling via the CB1 receptor has mixed effects on longevity


Serotonin is noted to possess potential antilongevity mechanisms, with mutants deficient in serotonin having greater nuclear accumulation of DAF-16 that is treated with exogenous serotonin or an SSRI.[39] This is dependent on ADF chemosensory neurons and through daf-2 (insulin receptor) and appears to share signalling properties with the IIS pathway,[39] and serotonin itself and antipsychotics have been linked to activating Akt (upstream of TOR) secondary to augmenting insulin receptor signalling.[62][39]

Serotonin appears to augment signalling via IIS, TOR, and the subsequent reduction in DAF-16 nuclear accumulation and impaired FOXO signalling; serotonin may not be per se anti-longevity but merely augment the efficacy of other pathways, but still appears to be involved


A reduction in sphingolipid synthesis in yeast has been shown to increase lifespan via Sch9 (S6K human homolog[63]) dependent mechanisms,[64] Sch9/S6K being downstream of IIS/TOR, and possibly secondary to activation of Pkh1/2 in yeast[65][66] which are known to activate Sch9.[64]

Sphingolipids are negative regulators of longevity secondary to activating S6K, a protein downstream of TOR


The HECT E3 ubiquitin ligase WWP-1 appears to be a positive regulator of longevity, independent of the IIS pathway and able to induce longevity independent of caloric restriction.[67] Interestingly, reducing WWP-1 or increasing levels of a metabolically inactive form of WWP-1 is able to reduce the benefits of caloric restriction; the mandatory cofactor UBC-18 is also mandatory for caloric restriction benefits.

The benefits of overexpressing WWP-1 are abolished if PHA-4 is abolished, but the reduction in life is preserved with abolishign DAF-16; WWP-1 appears to be more related to FOXA metabolism than ISS signalling.[67]

Enzymes in the ubiquination pathway have been identified as a positive modulator of longevity in C. Elegans


SKN-1 is the C. Elegans homolog of the human Nrf gene,[68] and Nrf2 is involved in a signalling pathway with a cytoplasmic protein known as Keap1; when Keap1 is phosphorylated, it releases Nrf2 to the nucleus to act upon the antioxidant response element (ARE) and induce production of oxidative enzymes.[69] Nrf2 is induced by caloric restriction[70] and is thought to underlie some hormetic benefits of caloric restriction.[70]

Human Nrf2 (C. Elegans SKN-1) is a protein that signals for production of antioxidant enzymes and is activated by oxidative stress and fasting; a possible mechanistic link between caloric restriction and longevity


The Raf-1/MEK1/2/ERK1/2 pathway is a pathway that positively regulates autophagy as ERK1/2 phosphorylates Gα-interacting protein which accelerates the rate of GTP hydrolysis (via Gαi3 protein) which ultimately promotes autophagy;[71][72] this pathway is inhibited by amino acids and a nutrient surplus,[72] and is thought to be related to caloric restriction.

2Phenomena of Interest

2.1Cellular Senesence

Cellular senesence (or sensence) is the aging of an individual cell as assessed by phenotypical and metabolic changes that slow down or cease cell functioning.

Accumulation of senescent cells appears to contribute to age-related pathology, and clearance of senescent cells has been demonstrated to revert these pathological changes.[73]

Senesence is highly related to the tumor suppressor gene p16[74] and p16Ink4a appears to be a biomarker of sensecence,[73] abolishing this protein has been noted to attenuate age-related phenotypical changes selectively in the tissue where p16Ink4a is abolished[75] whereas the related protein p19Arf appears to preserve longevity (abolishing it augments aging).[75] p16Ink4a may accumulate following activation of PPARγ[76] and is induced by agonists such as rosiglitazone.[73][76]

2.2Mitochondrial Hormesis

The mechanism is depedent on pmk-1 in C. Elegans (human ortholog is the p38 MAP kinase)[77] and abolished by antioxidant compounds.[77]

Some compounds that induce minor damage to the mitochondria (indicative by mitochondrial oxidation) appear to promote lifespan; this includes low dose arsenic and lonidamine.[78][77]


Autophagy is the process of cellular structures being encapsulated and digested by autophagosomes in a manner similar to cellular recycling.[79][80] Autophagosomes can be formed from the endoplasmic reticulum of a cell (called an omegasome)[81] and the lipids that form the membrane of the autophagosome can be derived from either the mitochondria[82] or cytoplasmic membrane.[83] Autophagy can be microautophagic (not present in mammals), macroautophagic (major and selective autophagy of target damaged molecules), or chaperone-mediated autophagy[84] mediated by Hsc70 and co-chaperones.[85]

This process is mediated by autophagy-related proteins, of which over 30 have been identified,[86][87] and can occur under conditions of both nutrient surplus and nutrient deficit. In nutrient deficit, autophagy is nonselective and aims to provide substrate to a cells energy state; in a nutrient excess, cargo-specific protein targets damaged organelles for removal.[79]

Autophagy is a process of targeted cellular destruction that appears to act as quality control for a cell. In mammals it can be broken down into macroautophagy (which consists of the majority of the actions) or chaperone-mediated autophagy


Mitophagy is autophagy in application to mitochondria and is required for maintaining mitochondrial quality and function via recycling damaged mitochondria.[88][89] It is conducted either via micromitophagy (invagination of the vacuolar/lysosomal boundary membrane[90][91]) or macromitophagy (sequestering into autophagosomes[92][91]); only the latter appears to be involved in mammals, with both active in yeast.[93][94] Specifically, mitophagy is a cargo-specific autophagy rather than nonspecific.

Cells (yeast) without macromitophagy appear to have more enlarged mitochondria of round shape and shortened cristae,[95] and under periods of caloric restriction without mitophagy an apparent accumulation of dysfunctional mitochondria and subsequent oxidation is noted.[95] Mitophagy is proposed to maintain mitochondrial function and turnover over a long period of time,[96][95] and is immediately preceded by mitochondrial fission.[97][98]

Mitophagy is a cellular recycling of mitochondria that is requires for optimal long-term functioning of a cell

Mitophagy appears to be somewhat guided by NIX (NIP3-like protein X or BNIP3L)[93] with the yeast homolog of ATG32;[99] NIX is a protein that is located in the outer membrane of the mitochondria and can bind to LC3 and its homologue (GABARAP)[100][101] acting as a membrane receptor for mitophagy.

Parkin is a protein (E3 ubiquitin ligase) that is selectively translocated to the damaged mitochondria following stressors,[102] and Parkin overexpression appears to destroy damaged mitochondria without influencing normal ones.[103] Parkin is recruited to damaged mitochondria by PINK1, a protein that is normally metabolized in mitochondria but accumulates in damaged mitochondria secondary to less proteolysis[104] and PINK1 has the capacity to phosphorylate and activate Parkin[105][106] which then functions as a ubiquitin in the mitochondria outer membrane;[107][108][109][110] it is thought that Parkin targeting two proteins known as mitofusions (1 and 2)[111][112] which stimulates mitophagy.

Parkin and PINK1 appear to be target proteins highly involved in cargo-specific mitophagy

2.5Chaperone-mediated Autophagy

Chaperone mediated autophagy (CMA) is a selective autophagy process for cytosolic proteins by transporting proteins across the lysosomal membrane[113][114] and does not have the capacity to degrade organelles such as mitochondria;[85] CMA, like other autophagic processes, is activated by cellular stresses and nutrient restriction[114][85] but specifically nutrient deprivation activates nonselective macroautophagy and gradually switch to CMA during prolonged starvation.[115][116] CMA function declines with age,[113] can be activated by oxidative stress,[117] and the 20-30% of lysosomes that are functional with CMA under fed conditions increases to 60-80% after three days of starvation (rat liver homogenates).[117][118]

Chaperone mediated autophagy is a highly selective autophagic process mediated from the endoplasmic reticulum and maintains protein homeostasis in the cytoplasm (but not organelles) through protein unfolding responses

CMA tends to target proteins with a KFERQ-motif (such as IκBα, RNAase A, and c-Fos;[119][85] consisting of about 30% of target proteins[120]) although similar pentaamino motifs such as QREFK or VDKFQ are also recognized.[85] Starvation, which increases CMA activity, is known to reduce the amount of cytosolic proteins with KFERQ motifs[118] but not in skeletal muscle[121] nor neurons (although neurons have higher baseline CMA activity).[122]

These sequences that are expressed on cytosolic proteins are targeted by chaperones and co-chaperones, with the primary chaperone being Heat Shock Cognate protein of 70-kDa (Hsc70 or Hsp70[123][124]) which also appears to be present in lysosomes[125] and Hsc90 which is mostly associated with the luminal side;[126] both proteins (Hsc70 and Hsc90) are chaperones that participate in protein unfolding.[85][124]

Chaperones also target lysosomes via the glycoprotein receptor known as LAMP-2A[127] (no affinity for LAMP-2B or 2C[128]) and the rate limiting step in CMA appears to be expression of LAMP-2A;[127] genetically ablating lamp-1A is lethal.[129]

Chaperones target cytoplasmic proteins via an amino acid binding sequence and then target the LAMP-2A receptor on lysosomes, bringing together the lysosome and protein for degradation.

Protein degradation is known to slow with aging[130] which leads to accumulation of altered or damaged proteins associated with reductions in chaperone mediated autophagy (among other things, but thought to play a causative role).[130][85] Senescent fibroblasts appear to have reduced CMA activity that is no longer able to be upregulated by serum starvation[131] (intrigueing, due to some molecules such as curcumin acting via caloric restriction-like mechanisms but being unable to benefit older persons) and has been noted in vivo.[132] It appears that the rate limiting step, LAMP-2A receptor expression, is downregulated which causes reductions in CMA rate of proteolysis[132] and is not due to transcriptional downregulation or changes in rates of synthesis and delivery of this receptor to the lysosomal compartment[85][133] but rather due to dynamics and stability at the lysosomal membrane being reduced with age.[133]

Genetically restoring LAMP-2A activity to older rats is able to remove age-related comorbidities and reduce oxidative damage in liver cells secondary to preserving CMA function.[134] LAMP-2A has been demonstrated to be downregulated in high-fat fed mice[135] but beyond that the mechanisms underlying the increased membrane instability of LAMP-2A (and reduction of activity with age) are largely unknown.

LAMP-2A downregulation provides a basis for how caloric restriction influences youth more than older individuals, and plays a crucial role in CMA

3Caloric Restriction

Currently, caloric restriction is the most reliable method of promoting longevity known and as such is usually reference in all longevity research

3.1Mechanisms involved in Caloric Restriction

Deletion of a gene (atg32Δ) that regulates mitophagy appears to prevent caloric restriction from promoting longevity in yeast.[95] 

The essential co-regulator of DAF-16, smk-1,[17] and FOX(A) signalling[136][137] appear to be vital for caloric restriction related longevity[24] despite DAF-16 nuclear accumulation (and FOXO signalling) per se not being mandatory.[136][137]

4Physical Exericse

4.1Chaperone-Mediated Autophagy

Exercise is able to increase mRNA translation of Hsp72[138] as Hsp72 is increase following oxidative, heat, hypoxic/hyperoxic and physical damage to tissue;[139] this increase has been noted in the liver,[140] heart,[141] leukocytes,[142][143] and adrenal glands[144] in addition to the exercised skeletal muscle[145][146][147] and the mechanism of activation is that muscle metabolism byproducts (lactate,[148] radicals, and glucose deprivation[149]) and stress hormones[150][151] phosphorylate a protein known as heat shock factor-1 (HSF-1) which becomes a trimer when phosphorylated and signals via the genome and produces Hsp72.[152] Hsp72 works in manners similar to other molecular chaperones and acts to degrade proteins in the cytoplasm and maintain cellular protein homeostasis[152][138] and the amount it is induced by exercise seems to correlate with the amount of metabolic damage the tissue undergoes (upregulated for 30 minutes following an hour of running and up to 24 hours after a marathon[138]) and is upregulated more when exercising in the heat.

Increasing Hsp72 expression in skeletal muscle is thought to be protective against pathology and aging[153] and does not appear to be increased during caloric restriction[154] like Hsp90 is increased.[155]

Exercise can stimulate molecular chaperones to promote cellular homeostasis of proteins in a similar manner to chaperone-mediated autophagy. The chaperones involved in the stress response to exercise appear to be different than those involved in caloric restriction

5Supplements that Interact with Longevity


Melatonin is a pineal hormone best known for its role in sleep, and appears to be highly involved with longevity (can be read on the Melatonin supplement page) in both a preventative and rehabilitative manner.

Melatonin has shown efficacy in nematodes, fruit flies, and mammals (rats and mice) with feasible oral doses of 5.45mg (150lb human equivalent, based off 1mg/kg in rats) taken daily. At least according to rat studies, 10-fold the dose confers no additional protective properties and is largely equivalent.

Although the mechanism is not known, it is thought to either be direct via inhibition of telomerase or indirect secondary to the pineal gland.

Melatonin supplementation is likely to be a feasible and safe longevity promoting agent that is feasible to take daily. Repeated trials have shown longevity promoting effects in mammalian species


Both Rhodiola Rosea and Eleutherococcus senticosus have been implicated in promoting heat resistance and longevity in drosophilia, which is thought to be related to DAF-16 signalling (as this molecule mediates both heat resistance in drosophilia and longevity) and indepedent of any losses in fecundity or caloric restriction. Both adaptogen compounds listed were shown to reduce lifespan in 10-fold the oral dose.

Adaptogens appear to induce longevity secondary to DAF-16 nuclear accumulation, which is independent of caloric restriction. Currently no mammalian research

5.3Lithocholic Acid

Lithocholic Acid (LCA) is a bile acid that appears to be synergistic with caloric restriction in promoting longevity in yeast[156] related to mitophagy, as abolishing macromitophagy abolished the synergism.[95] LCA appears to work independently of TOR and cAMP/PKA signalling (abolishing Rim15 failed to prevent the effects),[156] and only works during certain life phases of yeast.[157] It should be mentioned that the authors hypothesized that the targets of LCA may be inhibited by TOR and cAMP/PKA activation.[156]

Possible explanations for the obeserved synergism include the interaction of FOXA proteins with bile acids[32] and a reduction of lipid (free fatty acid and diacylglycerol) accumulation on the endoplastmic reticulum[158] (as LCA was able to rescue age reducing impairments in beta-oxidation).[156]

Lithocholic acid appears to synergistically promote longevity with caloric restriction in yeast (currently no studies in mammals) possibly related to lipid dynamics and the endoplasmic reticulum

Lithocholic acid is known to activate the Vitamin D receptor,[159] the TGR5 bile acid receptor,[160][161] the PXR receptor,[162] and the FXRα receptor[163] although both the VDR and PXR require concentrations above 30μM to activate.[161] It should also be noted that lithocholic acid has demonstratable toxicity in rats when orally ingested at 0.03% of the diet.[164]

Although promising due to synergism demonstrated with caloric restriction, is too preliminary to draw conclusions in mammalian species. Molecular targets are not fully identified yet


Caffeine (xanthine in tea and coffee) is noted in yeast to promote lifespan by a mechanism that is dependent on CREB1 phosphorylation, TORC1 inhibition, and DAF-16 nuclear accumulation.


  1. ^ Zakian VA. Telomeres: beginning to understand the end. Science. (1995)
  2. ^ Harley CB, Villeponteau B. Telomeres and telomerase in aging and cancer. Curr Opin Genet Dev. (1995)
  3. ^ Hukezalie KR, Wong JM. Structure-Function Relationship and Biogenesis Regulation of the Human Telomerase Holoenzyme. FEBS J. (2013)
  4. ^ a b Podlevsky JD, Chen JJ. It all comes together at the ends: telomerase structure, function, and biogenesis. Mutat Res. (2012)
  5. ^ Egan ED, Collins K. Specificity and stoichiometry of subunit interactions in the human telomerase holoenzyme assembled in vivo. Mol Cell Biol. (2010)
  6. ^ Kiss T, Fayet-Lebaron E, Jády BE. Box H/ACA small ribonucleoproteins. Mol Cell. (2010)
  7. ^ Fu D, Collins K. Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol Cell. (2003)
  8. ^ Raices M, et al. Uncoupling of longevity and telomere length in C. elegans. PLoS Genet. (2005)
  9. ^ Bernardes de Jesus B, et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell. (2011)
  10. ^ a b Lee RY, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol. (2001)
  11. ^ a b Mukhopadhyay A, Oh SW, Tissenbaum HA. Worming pathways to and from DAF-16/FOXO. Exp Gerontol. (2006)
  12. ^ a b Ogg S, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. (1997)
  13. ^ a b Gomes AR, Brosens JJ, Lam EW. Resist or die: FOXO transcription factors determine the cellular response to chemotherapy. Cell Cycle. (2008)
  14. ^ FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK.
  15. ^ Choi SL, et al. The regulation of AMP-activated protein kinase by H(2)O(2). Biochem Biophys Res Commun. (2001)
  16. ^ Sandström ME, et al. Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle. J Physiol. (2006)
  17. ^ a b Wolff S, et al. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell. (2006)
  18. ^ a b c McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell. (2003)
  19. ^ Corton JC, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci. (2005)
  20. ^ Lee SS, et al. DAF-16 target genes that control C. elegans life-span and metabolism. Science. (2003)
  21. ^ Oh SW, et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat Genet. (2006)
  22. ^ Kaestner KH. The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev. (2010)
  23. ^ Horner MA, et al. pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in Caenorhabditis elegans. Genes Dev. (1998)
  24. ^ a b c Panowski SH, et al. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature. (2007)
  25. ^ Mango SE. The molecular basis of organ formation: insights from the C. elegans foregut. Annu Rev Cell Dev Biol. (2009)
  26. ^ In Vitro and In Vivo Characterization of Caenorhabditis elegans PHA-4/FoxA Response Elements.
  27. ^ Gao N, et al. The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol Endocrinol. (2003)
  28. ^ Lupien M, et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell. (2008)
  29. ^ Carroll JS, et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. (2005)
  30. ^ Bernardo GM, et al. FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis. Development. (2010)
  31. ^ Zhang L, et al. Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Cell Metab. (2005)
  32. ^ a b Bochkis IM, et al. Foxa2-dependent hepatic gene regulatory networks depend on physiological state. Physiol Genomics. (2009)
  33. ^ Kenyon C, et al. A C. elegans mutant that lives twice as long as wild type. Nature. (1993)
  34. ^ Tu MP, Epstein D, Tatar M. The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell. (2002)
  35. ^ Clancy DJ, et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science. (2001)
  36. ^ Clancy DJ, et al. Dietary restriction in long-lived dwarf flies. Science. (2002)
  37. ^ a b c Henderson ST, Johnson TE. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. (2001)
  38. ^ Lin K, et al. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. (1997)
  39. ^ a b c d Liang B, et al. Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab. (2006)
  40. ^ Lin K, et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. (2001)
  41. ^ Vander Haar E, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. (2007)
  42. ^ Inoki K, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. (2002)
  43. ^ Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. (2002)
  44. ^ Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. (2006)
  45. ^ Long X, et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol. (2002)
  46. ^ Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. (2004)
  47. ^ a b Sheaffer KL, Updike DL, Mango SE. The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol. (2008)
  48. ^ a b Wang T, et al. LST8 regulates cell growth via target-of-rapamycin complex 2 (TORC2). Mol Cell Biol. (2012)
  49. ^ Evans DS, et al. TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing Res Rev. (2011)
  50. ^ Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. (2011)
  51. ^ Updike DL, Mango SE. Genetic suppressors of Caenorhabditis elegans pha-4/FoxA identify the predicted AAA helicase ruvb-1/RuvB. Genetics. (2007)
  52. ^ Long X, et al. Rheb binds and regulates the mTOR kinase. Curr Biol. (2005)
  53. ^ Saucedo LJ, et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. (2003)
  54. ^ Stocker H, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol. (2003)
  55. ^ Zhang Y, et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. (2003)
  56. ^ Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell. (2001)
  57. ^ Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids.
  58. ^ The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.
  59. ^ Kalender A, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. (2010)
  60. ^ Lucanic M, et al. N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature. (2011)
  61. ^ Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
  62. ^ Weeks KR, Dwyer DS, Aamodt EJ. Antipsychotic drugs activate the C. elegans akt pathway via the DAF-2 insulin/IGF-1 receptor. ACS Chem Neurosci. (2010)
  63. ^ Selman C, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. (2009)
  64. ^ a b Huang X, Liu J, Dickson RC. Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet. (2012)
  65. ^ Dickson RC. Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast. J Lipid Res. (2008)
  66. ^ Breslow DK, Weissman JS. Membranes in balance: mechanisms of sphingolipid homeostasis. Mol Cell. (2010)
  67. ^ a b Carrano AC, et al. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature. (2009)
  68. ^ Staab TA, et al. The Conserved SKN-1/Nrf2 Stress Response Pathway Regulates Synaptic Function in Caenorhabditis elegans. PLoS Genet. (2013)
  69. ^ Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. (2006)
  70. ^ a b Hine CM, Mitchell JR. NRF2 and the Phase II Response in Acute Stress Resistance Induced by Dietary Restriction. J Clin Exp Pathol. (2012)
  71. ^ Erk1/2-dependent Phosphorylation of Gα-interacting Protein Stimulates Its GTPase Accelerating Activity and Autophagy in Human Colon Cancer Cells.
  72. ^ a b Amino Acids Interfere with the ERK1/2-dependent Control of Macroautophagy by Controlling the Activation of Raf-1 in Human Colon Cancer HT-29 Cells.
  73. ^ a b c Baker DJ, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. (2011)
  74. ^ Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. (2012)
  75. ^ a b Baker DJ, et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. (2008)
  76. ^ a b PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts.
  77. ^ a b c Schmeisser S, Zarse K, Ristow M. Lonidamine extends lifespan of adult Caenorhabditis elegans by increasing the formation of mitochondrial reactive oxygen species. Horm Metab Res. (2011)
  78. ^ Schmeisser S, et al. Mitochondrial Hormesis Links Low-Dose Arsenite Exposure to Lifespan Extension. Aging Cell. (2013)
  79. ^ a b Eaten alive: a history of macroautophagy.
  80. ^ Nakatogawa H, et al. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol. (2009)
  81. ^ Axe EL, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. (2008)
  82. ^ Hailey DW, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. (2010)
  83. ^ Ravikumar B, et al. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol. (2010)
  84. ^ Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. (2011)
  85. ^ a b c d e f g h Orenstein SJ, Cuervo AM. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol. (2010)
  86. ^ Klionsky DJ, et al. A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy. (2011)
  87. ^ Klionsky DJ, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell. (2003)
  88. ^ Vazquez-Martin A, et al. Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: new insight into the role of mitophagy in cell stemness. Aging (Albany NY). (2012)
  89. ^ Yen WL, Klionsky DJ. How to live long and prosper: autophagy, mitochondria, and aging. Physiology (Bethesda). (2008)
  90. ^ Bhatia-Kiššová I, Camougrand N. Mitophagy in yeast: actors and physiological roles. FEMS Yeast Res. (2010)
  91. ^ a b The Many Faces of Mitochondrial Autophagy: Making Sense of Contrasting Observations in Recent Research.
  92. ^ Kanki T, Klionsky DJ, Okamoto K. Mitochondria autophagy in yeast. Antioxid Redox Signal. (2011)
  93. ^ a b Mechanisms of mitophagy.
  94. ^ Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J. (2012)
  95. ^ a b c d e Richard VR, et al. Macromitophagy is a longevity assurance process that in chronologically aging yeast limited in calorie supply sustains functional mitochondria and maintains cellular lipid homeostasis. Aging (Albany NY). (2013)
  96. ^ Tal R, et al. Aup1p, a yeast mitochondrial protein phosphatase homolog, is required for efficient stationary phase mitophagy and cell survival. J Biol Chem. (2007)
  97. ^ Mitochondrial fusion and fission in cell life and death.
  98. ^ Twig G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. (2008)
  99. ^ Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. (2013)
  100. ^ Novak I, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. (2010)
  101. ^ Schwarten M, et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy. (2009)
  102. ^ Narendra D, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. (2008)
  103. ^ Suen DF, et al. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc Natl Acad Sci U S A. (2010)
  104. ^ Narendra DP, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. (2010)
  105. ^ Kim Y, et al. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun. (2008)
  106. ^ Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet. (2010)
  107. ^ PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.
  108. ^ Geisler S, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. (2010)
  109. ^ Lee JY, et al. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol. (2010)
  110. ^ Narendra D, et al. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. (2010)
  111. ^ Gegg ME, et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. (2010)
  112. ^ Tanaka A, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol. (2010)
  113. ^ a b Cuervo AM. Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol Metab. (2010)
  114. ^ a b Dice JF. Chaperone-mediated autophagy. Autophagy. (2007)
  115. ^ Fuertes G, et al. Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. Biochem J. (2003)
  116. ^ Massey AC, et al. Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A. (2006)
  117. ^ a b Kiffin R, et al. Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell. (2004)
  118. ^ a b Cuervo AM, et al. Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol. (1995)
  119. ^ Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci. (1990)
  120. ^ Chiang HL, Dice JF. Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem. (1988)
  121. ^ Wing SS, et al. Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J. (1991)
  122. ^ Cuervo AM. Autophagy: many paths to the same end. Mol Cell Biochem. (2004)
  123. ^ Chiang HL, et al. A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science. (1989)
  124. ^ a b Agarraberes FA, Dice JF. A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci. (2001)
  125. ^ Agarraberes FA, Terlecky SR, Dice JF. An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol. (1997)
  126. ^ Bandyopadhyay U, et al. The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol. (2008)
  127. ^ a b Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. (1996)
  128. ^ Cuervo AM, Dice JF. Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci. (2000)
  129. ^ LAMP proteins are required for fusion of lysosomes with phagosomes.
  130. ^ a b Cuervo AM. Autophagy and aging: keeping that old broom working. Trends Genet. (2008)
  131. ^ Dice JF. Altered degradation of proteins microinjected into senescent human fibroblasts. J Biol Chem. (1982)
  132. ^ a b Cuervo AM, Dice JF. Age-related decline in chaperone-mediated autophagy. J Biol Chem. (2000)
  133. ^ a b Kiffin R, et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci. (2007)
  134. ^ Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med. (2008)
  135. ^ Rodriguez-Navarro JA, et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc Natl Acad Sci U S A. (2012)
  136. ^ a b Houthoofd K, et al. Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans. Exp Gerontol. (2003)
  137. ^ a b Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A. (1998)
  138. ^ a b c Yamada P, et al. Heat shock protein 72 response to exercise in humans. Sports Med. (2008)
  139. ^ Fehrenbach E, Northoff H. Free radicals, exercise, apoptosis, and heat shock proteins. Exerc Immunol Rev. (2001)
  140. ^ Exercise induces hepatosplanchnic release of heat shock protein 72 in humans.
  141. ^ Skidmore R, et al. HSP70 induction during exercise and heat stress in rats: role of internal temperature. Am J Physiol. (1995)
  142. ^ Fehrenbach E, et al. Changes of HSP72-expression in leukocytes are associated with adaptation to exercise under conditions of high environmental temperature. J Leukoc Biol. (2001)
  143. ^ Fehrenbach E, et al. HSP expression in human leukocytes is modulated by endurance exercise. Med Sci Sports Exerc. (2000)
  144. ^ Hung CH, et al. Progressive exercise preconditioning protects against circulatory shock during experimental heatstroke. Shock. (2005)
  145. ^ Febbraio MA, Koukoulas I. HSP72 gene expression progressively increases in human skeletal muscle during prolonged, exhaustive exercise. J Appl Physiol. (2000)
  146. ^ Vogt M, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. (2001)
  147. ^ Liu Y, et al. Human skeletal muscle HSP70 response to training in highly trained rowers. J Appl Physiol. (1999)
  148. ^ Peart DJ, et al. Pre-exercise alkalosis attenuates the heat shock protein 72 response to a single-bout of anaerobic exercise. J Sci Med Sport. (2011)
  149. ^ Febbraio MA, et al. Glucose ingestion attenuates the exercise-induced increase in circulating heat shock protein 72 and heat shock protein 60 in humans. Cell Stress Chaperones. (2004)
  150. ^ Maloyan A, Horowitz M. beta-Adrenergic signaling and thyroid hormones affect HSP72 expression during heat acclimation. J Appl Physiol. (2002)
  151. ^ Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response.
  152. ^ a b Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol. (2002)
  153. ^ Gehrig SM, et al. Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature. (2012)
  154. ^ Colotti C, et al. Effects of aging and anti-aging caloric restrictions on carbonyl and heat shock protein levels and expression. Biogerontology. (2005)
  155. ^ Selsby JT, et al. Life long calorie restriction increases heat shock proteins and proteasome activity in soleus muscles of Fisher 344 rats. Exp Gerontol. (2005)
  156. ^ a b c d Goldberg AA, et al. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging (Albany NY). (2010)
  157. ^ Burstein MT, et al. Lithocholic acid extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan. Cell Cycle. (2012)
  158. ^ Beach A, Titorenko VI. In search of housekeeping pathways that regulate longevity. Cell Cycle. (2011)
  159. ^ Makishima M, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. (2002)
  160. ^ Keitel V, et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia. (2010)
  161. ^ a b Pols TW, et al. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis. (2011)
  162. ^ Staudinger JL, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. (2001)
  163. ^ Makishima M, et al. Identification of a nuclear receptor for bile acids. Science. (1999)
  164. ^ Song P, Zhang Y, Klaassen CD. Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice. Toxicol Sci. (2011)