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Cited by 345Genetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and SenescenceSirtuins and Resveratrol in Medicine

The Search for Antiaging Interventions: From Elixirs to Fasting Regimens

Open access
de Cabo, Rafael, Carmona-Gutierrez, Didac, Bernier, Michel, Hall, Michael N., Madeo, Frank·2014·Cell
DOI 10.1016/j.cell.2014.05.031PMC PMC4254402
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Abstract

The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms.

AI snapshot

Written from the paper’s full text.

TL;DR

This review critically examines behavioral and pharmacological antiaging interventions that meet stringent criteria of healthspan/lifespan extension, validation in at least three model organisms, and confirmation by at least three laboratories. It concludes that the most effective interventions converge on nutrient signaling, mitochondrial efficiency, proteostasis, autophagy, and stress resistance, while human applicability remains uncertain.

Key findings

  • Caloric restriction (CR) extends mean and maximum lifespan in dogs, rodents, worms, flies, yeasts, and prokaryotes; in rodents, moderate CR (8%) affects median but not maximal lifespan, whereas more severe CR (30%) increases lifespan by up to 50%. In humans, CR of around 15% may be most favorable against mortality during aging, but prolonged severe CR is linked to side effects including decreased fertility, wound healing problems, amenorrhea, osteoporosis, and reduced infection resistance.
  • Fasting regimens show antiaging and healthspan effects: rats on alternate-day fasting live up to 83% longer than normally fed counterparts, and a 24-hour fast every 4 days is sufficient to promote significant lifespan extension; a 5-day fast lowers IGF1 plasma levels by more than 60%. A two-week medically supervised water-only fast resulted in blood pressure below 120/80 mm Hg in 82% of subjects with borderline hypertension, and 10 days of water-only fasting normalized blood pressure in all hypertensive patients taking antihypertensive medication.
  • Pharmacological candidates include rapamycin, resveratrol, spermidine, and metformin. Rapamycin extends lifespan in yeast, flies, worms, and mice; resveratrol prolongs lifespan of mice on a high-fat diet or fed every other day but not mice on regular chow; spermidine triggers autophagy and extends lifespan in yeast, flies, and worms; metformin increases mean and maximum lifespan in different female mouse strains predisposed to high mammary tumor incidence.
  • Common molecular denominators include insulin/IGF1/TOR signaling, autophagy, hormesis, and mitochondrial function; autophagy induction, improved stress resistance, and mitochondrial efficiency are proposed as key cellular functions needed to delay aging features such as free radical generation, excess caloric intake, chronic hyperglycemia, and fat accumulation.

Methods

  • Design: narrative review that considers only pharmacological interventions, regimens, and genetic manipulations meeting three selective criteria: promotion of healthspan and/or life extension, validation in at least three model organisms, and confirmation by at least three different laboratories.
  • Data/sample: literature on fasting regimens, caloric restriction, exercise, and low-molecular-weight compounds including spermidine, metformin, resveratrol, and rapamycin, with evidence from yeast, worms, flies, rodents, non-human primates, and humans.
  • Main analysis: critical evaluation of proposed antiaging interventions and their underlying molecular mechanisms, including epigenetic mechanisms, insulin/TOR and Ras signaling, mitochondrial function, proteostasis, autophagy, and stress resistance.

Limitations

  • The paper states that only a few proposed aging interventions met its stringent criteria, that aging research has relatively low reproducibility because aging is a long-lasting process prone to artifacts, and that some inconsistencies arise from over-interpretation of lifespan-shortening scenarios.
  • The paper states that CR studies in non-human primates produced different outcomes, that human applicability of these interventions remains unclear, and that more research is needed on long-term effects alone and in combination.
  • Evident from the text: this is a narrative review without a described systematic search or meta-analysis, and it reports no new experimental data; its 2014 publication date also means later evidence is not included.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2014.05.031

Cites

124 of 124 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 99 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Resveratrol does not prolong yeast chronological lifespan.

    “but not yeast’s chronological lifespan (our unpublished observations).”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    Only a few proposed aging interventions have met the stringent criteria of healthspan/life extension, validation in at least three model organisms, and confirmation by at least three different laboratories: fasting regimens, caloric restriction, exercise, and the use of low molecular weight compounds including spermidine, metformin, resveratrol and rapamycin.

    “There are only a few proposed aging interventions that have met such stringent criteria: fasting regimens, caloric restriction, exercise, and the use of low molecular weight compounds, including spermidine, metformin, resveratrol and rapamycin (Table 1).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The three criteria used to select interventions (healthspan/life extension, validation in at least three model organisms, and confirmation by at least three different laboratories) are sufficient to identify reliable anti-aging interventions.
  • Premisecitation

    Healthspan has not increased at the same pace as lifespan.

    “The fact that healthspan has not increased at the same pace as lifespan is a source of grave concern (Mercken et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mercken et al., 2012 source

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  • Interpretationnone given

    The most effective anti-aging interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy.

    “Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    One problem in aging research is the relatively low reproducibility of experimental findings due to aging being a long-lasting process.

    “One of the problems in aging research is the relatively low reproducibility of experimental findings due to the simple fact that aging is a long-lasting process.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Interpretationnone given

    Low caloric regimes and exercise may improve healthy senescence.

    “Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The molecular mechanisms underlying aging-associated defects appear to be interconnected and affect the same pathways as those responsible for cancer, cardiovascular and neurodegenerative disorders.

    “Indeed, the molecular mechanisms underlying aging-associated defects appear to be interconnected and affect the same pathways as those responsible for diseases such as cancer, cardiovascular and neurodegenerative disorders.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Age itself remains the greatest risk factor for all major life-threatening disorders.

    “However, according to the WHO, age itself remains the greatest risk factor for all major life-threatening disorders, and the number of people suffering from age-related diseases is anticipated to almost double over the next two decades.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites WHO

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    These interventions may act through epigenetic mechanisms, the insulin/TOR pathway, the Ras signaling pathway, mitochondrial function, proteostasis, autophagy, and stress resistance.

    “From a molecular point of view, these interventions may act through epigenetic mechanisms (histone acetylation/methylation), the insulin/TOR pathway, the Ras signaling pathway, mitochondrial function, proteostasis, autophagy, and stress resistance.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from model organisms about lifespan or healthspan extension can be extrapolated to humans.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    The existence of some programmatic features during aging is a conditio sine qua non for a therapeutic approach to combat aging.

    “The existence of some programmatic features during aging is a conditio sine qua non for a therapeutic approach to combat aging.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Among these pathways are the insulin and the TOR/S6K pathways, whose inhibition upon CR eventually confers stress resistance and promotes survival during aging.

    “Among them are the insulin and the TOR/S6K pathways, whose inhibition upon CR eventually confer stress resistance and promote survival during aging.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fontana et al., 2010 source

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    Premisecitation

    In rodents, moderate CR (8%) positively affects median (not maximal) lifespan, but a more severe (30%) dietary restriction increases lifespan by up to 50%, partly by delaying the emergence of chronic diseases.

    “Of note, in rodents, moderate CR (8%) positively affects median (not maximal) lifespan, but a more severe (30%) dietary restriction increases lifespan by up to 50%, partly by delaying the emergence of chronic diseases (Anderson et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Anderson et al., 2009 source

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    Interpretationreasoning

    Aging may be an atavistic, adaptive and altruistic program, by which single cells or organisms eventually die for the benefit of the whole population in a highly coordinated fashion.

    “This implies that aging may be an atavistic, adaptive and altruistic program, by which single cells or organisms eventually die for the benefit of the whole population in a highly coordinated (programmatic) fashion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In unicellular organisms, nutrient deprivation triggers lifespan extension to probably maximize the chances of reproduction in the event of future exposure to a nutrient-rich environment.

    “In unicellular organisms, nutrient deprivation triggers lifespan extension to probably maximize the chances of reproduction in the event of future exposure to a nutrient-rich environment.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Genetic disruption of PCD-mediated cell removal improves short-term survival of aged cultures; however, the surviving cells lose their ability to re-grow, indicating an accumulation of damaged cells in the absence of PCD.

    “Genetic disruption of PCD-mediated cell removal improves short-term survival of aged cultures; however, the surviving cells lose their ability to re-grow, indicating an accumulation of damaged cells in the absence of PCD (Fabrizio et al., 2004; Herker et al., 2004).”
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    Premisecitation

    CR reduces the release of growth factors like growth hormone, insulin and insulin-like growth factor 1 (IGF1), which have been shown to accelerate aging and increase mortality in many organisms.

    “CR reduces the release of growth factors like growth hormone, insulin and insulin-like growth factor 1 (IGF1), which have been shown to accelerate aging and increase mortality in many organisms (Fontana et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fontana et al., 2010 source

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    Premisecitation

    As opposed to CR, periodic fasting is psychologically more viable, lacks some of the negative side effects and is only accompanied by minimal weight loss.

    “As opposed to CR, periodic fasting is psychologically more viable, lacks some of the negative side effects and is only accompanied by minimal weight loss (Heilbronn et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Heilbronn et al., 2005 source

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    Premisecitation

    A number of fasting regimens are asserting themselves as suitable strategies, among them the alternate day fasting diet, the '5:2' intermittent fasting diet, and a 48-hour fast once or twice each month.

    “A number of fasting regimens are asserting themselves as suitable strategies, among them the alternate day fasting diet (Johnson et al., 2007; Varady et al., 2009), the ‘5:2’ intermittent fasting diet (Harvie et al., 2011), and a 48-hour fast once or twice each month.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Johnson et al., 2007 source

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    • cites Varady et al., 2009 source

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    Premisecitation

    Two studies have addressed the effects of CR on non-human primates, but with different outcomes: one observed prolonged life while the other did not.

    “Two studies have addressed the effects of CR on non-human primates, but with different outcomes. One study observed prolonged life (Colman et al., 2009) while the other did not (Mattison et al., 2012).”
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    • cites Mattison et al., 2012 source

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    Premisecitation

    Prolonged CR may decrease fertility and libido, create wound healing problems, and result in amenorrhea, osteoporosis, and decreased potential to combat infections.

    “Studies have shown that prolonged CR may decrease fertility and libido, create wound healing problems, and result in amenorrhea, osteoporosis, and decreased potential to combat infections.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Epigenetic modifications observed during aging are another possible target of CR, although this is based largely on correlative data.

    “Epigenetic modifications observed during aging are another possible target of CR, although this is based largely on correlative data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The beneficial effects of CR may represent an adaptive response forged during evolution to overcome short-time famine conditions.

    “The beneficial effects of CR may represent an adaptive response forged during evolution to overcome short-time famine conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sustenance on a severely restricted diet without malnutrition (around 30% CR) is arduous and is linked to chronic low weight and substantial side effects.

    “Nevertheless, sustenance on a severely restricted diet without malnutrition (around 30% CR) is arduous and is linked to chronic low weight and substantial side effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both studies point to the fact that CR increases healthspan in monkeys by reducing the risk for diabetes, cardiovascular disease, and cancer.

    “However, both studies point to the fact that CR increases healthspan in monkeys by reducing the risk for diabetes, cardiovascular disease, and cancer.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Colman et al., 2009 source

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    • cites Mattison et al., 2012 source

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    Premisecitation

    Okinawan people usually combine an above-average amount of daily exercise with a below-average food intake.

    “In comparison to the rest of the Japanese population, Okinawan people usually combine an above-average amount of daily exercise with a below-average food intake (Willcox and Willcox, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Willcox and Willcox, 2014

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    Premisenone given

    Food deprivation in adults during World War II in some European countries has been associated with long term health span, but also with detrimental effects.

    “Interestingly, food deprivation in adults during World War II in some European countries has been associated with long term health span, but also with detrimental effects.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    When Okinawan families moved to Brazil, they adopted a Western lifestyle that impacted both their diet and physical activity, resulting in increased weight gain and a drop in life expectancy of 17 years.

    “However, when Okinawan families moved to Brazil, they adopted a Western lifestyle that impacted both their diet and physical activity, resulting in increased weight gain and a drop in life expectancy of 17 years (Mizushima et al., 1997).”
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    • cites Mizushima et al., 1997 source

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    Premisecitation

    A lower age-associated morbidity and a longer lifespan were observed among Spanish home nursing residents performing alternate day fasting, where residents fasted every other day with unrestricted food supply on the non-fasting day.

    “A lower age-associated morbidity and a longer lifespan were observed among Spanish home nursing residents performing alternate day fasting, where residents fasted every other day with unrestricted food supply on the non-fasting day (Mercken et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mercken et al., 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The quantitative impact of lifespan extension relative to the total, natural lifespan of an organism might be more prominent in short-lived species (like mice) than in long-lived ones (like primates).

    “In that case, the quantitative impact of lifespan extension relative to the total, natural lifespan of an organism might be more prominent in short-lived species (like mice) than in long-lived ones (like primates).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The healthier ad libitum diet in the NIA study allowed for longer lifespan in control animals without conferring additional benefit from CR.

    “In contrast, the healthier ad libitum diet in the NIA study (Mattison et al., 2012) allowed for longer lifespan in control animals without conferring additional benefit from CR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mattison et al., 2012 source

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    Premisecitation

    CR changes many parameters in the aging human body, including the transcriptome, the hormonal status (in particular the serum concentration of IGF-1 and thyroid hormones), oxidative stress, inflammation, mitochondrial function, and glucose homeostasis.

    “CR changes many parameters in the aging human body, including the transcriptome, the hormonal status (in particular the serum concentration of IGF-1 and thyroid hormones), oxidative stress, inflammation, mitochondrial function, and glucose homeostasis (Fontana et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fontana et al., 2010 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    This form of feeding pattern may actually reflect mammalian adaptation to food, for example, overeating in times of nutrient abundance and starvation in between.

    “From an evolutionary point of view, this form of feeding pattern may actually reflect mammalian adaptation to food, for example, overeating in times of nutrient abundance (e.g. after a successful hunt) and starvation in between.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Native tribes live today, many of which showing no signs of age-associated diseases, such as cancer, neurodegeneration, diabetes, cardiovascular disease, or hypertension.

    “This is also how native tribes live today, many of which showing no signs of age-associated diseases, such as cancer, neurodegeneration, diabetes, cardiovascular disease, or hypertension (Gurven et al., 2009).”
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    Premisecitation

    Periodic fasting dampens the deleterious consequences of Alzheimer's, Parkinson's, and Huntington's diseases as well as frontotemporal dementia in various mouse models, without beneficial effect on amyotrophic lateral sclerosis.

    “Periodic fasting dampens the deleterious consequences of Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as frontotemporal dementia in various mouse models, without beneficial effect on amyotrophic lateral sclerosis (Longo and Mattson, 2014).”
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    • cites Longo and Mattson, 2014

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    Interpretationreasoning

    While fasting may prolong life in adult humans, the results with monkeys are still contentious.

    “While fasting may prolong life in adult humans, the results with monkeys are still contentious (see above).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    When combined with chemotherapy, a 2-to-3-day fast enhances efficacy of a variety of chemotherapeutic drugs while reducing their negative side effects in mice.

    “When combined with chemotherapy, a 2-to-3-day fast enhances efficacy of a variety of chemotherapeutic drugs while reducing their negative side effects in mice (Raffaghello et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Raffaghello et al., 2008 source

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    Premisecitation

    Rats on an alternate day fasting protocol live up to 83% longer than their normally fed counterparts, and a 24-hour fasting period every 4 days is sufficient to promote a significant lifespan extension.

    “Of note, rats on an alternate day fasting protocol live up to 83% longer than their normally fed counterparts, and a 24-hour fasting period every 4 days is sufficient to promote a significant lifespan extension (Longo and Mattson, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Longo and Mattson, 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Free fatty acids already appear in the bloodstream after fasting for 12-24 hours.

    “For instance, free fatty acids already appear in the bloodstream after fasting for 12–24 hours.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Mice that were fed a high-fat diet in a time-restricted manner, i.e. with regular fasting breaks, had lower inflammatory markers, no fatty liver and were slim in comparison to mice with equivalent total number of calories consumed ad libitum.

    “Of significance, mice that were fed a high-fat diet in a time-restricted manner, i.e. with regular fasting breaks, had lower inflammatory markers, no fatty liver and were slim in comparison to mice with equivalent total number of calories consumed ad libitum (Hatori et al., 2012).”
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    • cites Hatori et al., 2012 source

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    Interpretationreasoning

    Food shortage especially during the intrauterine phase and childhood may be more prone to cause malnutrition and thus result in a vast array of adverse effects.

    “Food shortage especially during the intrauterine phase and childhood may be more prone to cause malnutrition and thus result in a vast array of adverse effects.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The body's main source of energy then comes from ketolysis, which generates acetyl-CoA, and gluconeogenesis-dependent generation of approximately 80 g of glucose each day, which is mainly consumed by the brain.

    “The body’s main source of energy then comes from ketolysis, which generates acetyl-CoA, and gluconeogenesis-dependent generation of approximately 80 g of glucose each day, which is mainly consumed by the brain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    In stark contrast to normal cells, tumor cells never cease to proliferate and require enhanced glucose metabolism to meet their high energy and biosynthetic demands.

    “In stark contrast to normal cells, tumor cells never cease to proliferate and require enhanced glucose metabolism to meet their high energy and biosynthetic demands.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Aged men on an eating plan involving 2 days of fasting each week lose weight and experienced fewer bouts of depression.

    “Similarly, aged men on an eating plan involving 2 days of fasting each week lose weight and experienced fewer bouts of depression (Teng et al., 2011).”
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    Premisenone given

    A worldwide sociohistorical turn occurred in 2006 when the number of deaths related to obesity exceeded those linked to starvation.

    “A worldwide sociohistorical turn occurred in 2006 when the number of deaths related to obesity exceeded those linked to starvation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    While extremely obese people (BMI above 35) are at 29% higher risk of premature death, moderately overweight individuals seem to be protected, having lower overall mortality risk as compared to normal weight persons.

    “Of note, while extremely obese people (BMI above 35) are at 29% higher risk of premature death, moderately overweight individuals seem to be protected, having lower overall mortality risk as compared to normal weight persons (Flegal et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Flegal et al., 2013 source

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    Premisecitation

    The waist/hip ratio is a much better indicator for body fat and an excellent predictor of the odds of dying from cardiovascular diseases, with low waist/hip ratio associated with a lower mortality risk.

    “In fact, the waist/hip ratio is a much better indicator for body fat and an excellent predictor of the odds of dying from cardiovascular diseases, with low waist/hip ratio associated with a lower mortality risk (Welborn et al., 2003).”
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    • cites Welborn et al., 2003 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Fasting might even be harmful to certain individuals (e.g., children and underweight people) and in some disease states (e.g., type 1 diabetes or extreme hypertension), where fasting can result in severe health consequences and possible death unless performed under medical supervision.

    “It should also be noted that fasting might even be harmful to certain individuals (e.g., children and underweight people) and in some disease states (e.g., type 1 diabetes or extreme hypertension), where fasting can result in severe health consequences and possible death unless performed under medical supervision.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Moderately overweight individuals probably have better protection in times of disease/crisis and improved response against infections and toward wound healing.

    “Moderately overweight individuals probably have better protection in times of disease/crisis and improved response against infections and toward wound healing (Flegal et al., 2013).”
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    • cites Flegal et al., 2013 source

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    Interpretationnone given

    The efficacy of most fasting strategies as they relate to medical conditions and/or aging might be limited if they are not integrated with diets that have health-associated benefits, such as the Mediterranean diet or the Okinawa low protein diet.

    “However, the efficacy of most fasting strategies as they relate to medical conditions and/or aging might be limited if they are not integrated with diets that have health-associated benefits, such as the Mediterranean diet or the Okinawa low protein diet.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A 5-day fasting period lowers IGF1 plasma levels by more than 60% and causes a significant increase in IGFBP-1.

    “Most anti-aging regimens elicit a drop in circulating IGF1, as evidenced by the fact that a 5-day fasting period lowers IGF1 plasma levels by more than 60% and causes a significant increase in IGFBP-1, one of the principal IGF1-inhibiting proteins (Longo and Mattson, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Longo and Mattson, 2014

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    Premisecitation

    Rapamycin is a strong inducer of autophagy and extends lifespan in all organisms tested so far, including yeast, flies, worms and mice.

    “Rapamycin is a strong inducer of autophagy and it extends lifespan in all organisms tested so far, including yeast, flies, worms and mice (Bjedov and Partridge, 2011; Kapahi et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Resveratrol prolongs the life of flies, worms, and the replicative lifespan of yeast.

    “Resveratrol prolongs the life of flies (Bauer et al., 2004), worms (Baur and Sinclair, 2006), and the replicative lifespan of yeast (Howitz et al., 2003), but not yeast’s chronological lifespan (our unpublished observations).”
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    Premisecitation

    Resveratrol supplementation prolongs the lifespan of mice fed a high-fat diet or fed every other day, but not of mice on regular chow.

    “Resveratrol supplementation prolongs the lifespan of mice fed a high-fat diet or fed every other day (Baur et al., 2006), but not of mice on regular chow.”
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    • cites Baur et al., 2006

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    Premisecitation

    Spermidine is a naturally occurring polyamine that triggers autophagy and, thereby, lifespan extension when supplemented in the food supply of yeast, flies and worms.

    “Spermidine is a naturally occurring polyamine that triggers autophagy and, thereby, lifespan extension when supplemented in the food supply of yeast, flies and worms (Eisenberg et al., 2009).”
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    • cites Eisenberg et al., 2009 source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Autophagy up-regulation, improved stress resistance, and mitochondrial efficiency are among the cellular functions needed to hold off features associated with accelerated aging, such as free radical generation, excess caloric intake, chronic hyperglycemia, and fat accumulation.

    “Autophagy up-regulation, improved stress resistance and mitochondrial efficiency are among the cellular functions needed to hold off features associated with accelerated aging, such as free radical generation, excess caloric intake, chronic hyperglycemia, and fat accumulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Knocking down genes essential for autophagy abrogates lifespan extension in worms, arguing for a causal link between autophagy and longevity.

    “The fact that knocking down genes essential for autophagy abrogates lifespan extension in worms (Jia and Levine, 2007; Tavernarakis et al., 2008) argues for a causal link between autophagy and longevity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jia and Levine, 2007

      Not checked in the free run.

    • cites Tavernarakis et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fasting and exercise regimens, and a number of small molecules, are compatible with the concept of programmed aging and are amenable to interventions aimed at modulating molecular components and pathways responsible for the aging process.

    “All these interventions are compatible with the concept of programmed aging and, thus, amenable to interventions aimed at modulating molecular components and pathways responsible for the aging process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Transgenic mice overexpressing human catalase targeted solely to the mitochondria live longer and have less cardiac pathology.

    “In line with these results, transgenic mice overexpressing human catalase targeted solely to the mitochondria (not to the peroxisome or the nucleus) live longer and have less cardiac pathology (Schriner et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schriner et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, overexpression of Atg5, a gene essential for autophagy, is sufficient to activate autophagy and extend lifespan.

    “In mice, overexpression of Atg5, a gene essential for autophagy, is sufficient to activate autophagy and extend lifespan (Pyo et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pyo et al., 2013 source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    Findings from model organisms about lifespan or healthspan extension can be extrapolated to humans.

    “There are only a few proposed aging interventions that have met such stringent criteria: fasting regimens, caloric restriction, exercise, and the use of low molecular weight compounds, including spermidine, metformin, resveratrol and rapamycin (Table 1).”

  • The authors state this as an assumption.

    The three criteria used to select interventions (healthspan/life extension, validation in at least three model organisms, and confirmation by at least three different laboratories) are sufficient to identify reliable anti-aging interventions.

    “the present review considers only pharmacological interventions, regimens and genetic manipulations that meet three highly selective criteria: (i) promotion of healthspan and/or life extension; (ii) validation in at least three model organisms; and (iii) confirmation by at least three different laboratories.”

  • The paper relies on this without support.

    Long-term administration of rapamycin causes adverse health effects in patients, including impaired wound healing, anemia, proteinuria, pneumonitis, and hypercholesterolemia.

    “Moreover, long-term administration of rapamycin has been found to cause a variety of adverse health effects in patients, including impaired wound healing, anemia, proteinuria, pneumonitis, and hypercholesterolemia.”

  • The paper relies on this without support.

    Findings from model organisms about lifespan extension are informative about human aging and antiaging interventions.

    “Rapamycin is a strong inducer of autophagy and it extends lifespan in all organisms tested so far, including yeast, flies, worms and mice (Bjedov and Partridge, 2011; Kapahi et al., 2004).”

  • The paper relies on this without support.

    CR is a strong inducer of autophagy.

    “CR is a strong inducer of autophagy, which may be an efficient strategy to maintain life under times of scarce resources.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation, and inhibition of autophagy mimics accelerated aging.

    “Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation, and inhibition of autophagy mimics accelerated aging (52, 228, 229).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [52]

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Authors
de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M. N., & Madeo, F.
Affiliations
  • National Institutes of Health (US)
  • University of Basel (CH)
  • University of Graz (AT)
Corresponding author
Madeo, Frank
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2014-06
Volume
157
Issue
7
Pages
1515-1526
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2014.05.031
PMC
PMC4254402
OpenAlex
W2037782139
Semantic Scholar
9f20b1c990517481dd9b3a8a3cfdb037a7cc6f8e
Cited by
345
References
124
Citations by year
2026: 8 · 2025: 21 · 2024: 17 · 2023: 21 · 2022: 29 · 2021: 34 · 2020: 29 · 2019: 38 · 2018: 34 · 2017: 30 · 2016: 40 · 2015: 38 · 2014: 6
FWCI
4.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (ZIAAG000368)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
healthy aging, lifespan extension, healthspan, caloric restriction, physical activity, nutrient signaling, mitochondrial efficiency, proteostasis, autophagy
MeSH terms
Aging, Animals, Antioxidants, Autophagy, Diet, Humans, Longevity, Signal Transduction, Exercise

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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