The DOI matches its Crossref record; 124 of the 124 references it cites were found in a registry or an index; none of the 99 sources its claims cite is checked for support yet.
The Search for Antiaging Interventions: From Elixirs to Fasting Regimens
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but not yeast’s chronological lifespan (our unpublished observations).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Pharmacological anti-aging interventions
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 search for anti-aging interventions: From elixirs to fasting regimens > Introduction
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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.
In the paper
“The fact that healthspan has not increased at the same pace as lifespan is a source of grave concern (Mercken et al., 2012).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Introduction
What the sources say
- Not checked yetcites Mercken et al., 2012 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Introduction
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“For instance, recent evidence points toward a role of the mitochondrial sirtuin SIRT3 in the prevention of age-related diseases, possibly through modulation of the mitochondrial acetyl proteome (Hebert et al., 2013).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Hebert et al., 2013 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Within chronologically aged yeast cultures, single yeast cells induce programmed cell death (PCD) as a result of the accumulation of oxygen radicals and metacaspase activation (Fabrizio et al., 2004; Herker et al., 2004).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Why do we age?
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In that case, groups harboring individual cells or organisms capable of dying in times of stress (e.g., nutrient deprivation, starvation) would have a selective evolutionary advantage over groups in which every single cell or organism is selfish.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Why do we age?
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Since then, CR has been shown to prolong mean and maximum lifespan in dogs, rodents, worms, flies, yeasts, and prokaryotes (Fontana et al., 2010).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Fontana et al., 2010 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: Findings from model organisms about lifespan or healthspan extension can be extrapolated to humans.
In the paper
“In humans, there exists some indication that a CR of around 15% may be most favorable against mortality during aging (Willcox and Willcox, 2014).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Willcox and Willcox, 2014
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 40
- Probably not a substantial claim. 18
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Introduction
What the sources say
- Not checked yetcites WHO
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Introduction
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: Findings from model organisms about lifespan or healthspan extension can be extrapolated to humans.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The existence of some programmatic features during aging is a conditio sine qua non for a therapeutic approach to combat aging.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Why do we age?
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
In the paper
“Among them are the insulin and the TOR/S6K pathways, whose inhibition upon CR eventually confer stress resistance and promote survival during aging.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Fontana et al., 2010 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Anderson et al., 2009 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Why do we age?
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Why do we age?
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Fontana et al., 2010 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
- Not checked yetcites Heilbronn et al., 2005 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Epigenetic modifications observed during aging are another possible target of CR, although this is based largely on correlative data.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The beneficial effects of CR may represent an adaptive response forged during evolution to overcome short-time famine conditions.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, both studies point to the fact that CR increases healthspan in monkeys by reducing the risk for diabetes, cardiovascular disease, and cancer.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Willcox and Willcox, 2014
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Mizushima et al., 1997 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
- Not checked yetcites Mercken et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Mattison et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Caloric restriction
What the sources say
- Not checked yetcites Fontana et al., 2010 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
- Not checked yetcites Gurven et al., 2009 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Longo and Mattson, 2014
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While fasting may prolong life in adult humans, the results with monkeys are still contentious (see above).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Raffaghello et al., 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
- Not checked yetcites Longo and Mattson, 2014
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For instance, free fatty acids already appear in the bloodstream after fasting for 12–24 hours.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
What the sources say
- Not checked yetcites Hatori et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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 search for anti-aging interventions: From elixirs to fasting regimens > Behavioral anti-aging interventions > Dietary strategies based on CR
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Teng et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A worldwide sociohistorical turn occurred in 2006 when the number of deaths related to obesity exceeded those linked to starvation.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Flegal et al., 2013 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Welborn et al., 2003 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
What the sources say
- Not checked yetcites Flegal et al., 2013 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Healthy aging to combat diseases > Fasting
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Common molecular denominators > Insulin signaling
What the sources say
- Not checked yetcites Longo and Mattson, 2014
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 search for anti-aging interventions: From elixirs to fasting regimens > Pharmacological anti-aging interventions
What the sources say
- Not checked yetcites Bjedov and Partridge, 2011
- Not checked yetcites Kapahi et al., 2004 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Pharmacological anti-aging interventions
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Pharmacological anti-aging interventions
What the sources say
- Not checked yetcites Baur et al., 2006
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Pharmacological anti-aging interventions
What the sources say
- Not checked yetcites Eisenberg et al., 2009 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Conclusion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Common molecular denominators > Autophagy
What the sources say
- Not checked yetcites Jia and Levine, 2007
- Not checked yetcites Tavernarakis et al., 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Conclusion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Common molecular denominators > Mitochondrial function
What the sources say
- Not checked yetcites Schriner et al., 2005 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In mice, overexpression of Atg5, a gene essential for autophagy, is sufficient to activate autophagy and extend lifespan (Pyo et al., 2013).”
§ The search for anti-aging interventions: From elixirs to fasting regimens > Common molecular denominators > Autophagy
What the sources say
- Not checked yetcites Pyo et al., 2013 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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?
In the citing paper
“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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Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 7
- Pages
- 1515-1526
- ISSN
- 0092-8674 (ISSN-L)
- 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
- bronze
- doi.org
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
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