The Search for Antiaging Interventions: From Elixirs to Fasting Regimens

In the paper

“but not yeast’s chronological lifespan (our unpublished observations).”

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).”

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).”

What the sources say

• Not checked yetcites Mercken et al., 2012 source

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.”

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.”

In 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).”

What the sources say

• Not checked yetcites Hebert et al., 2013 source

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).”

What the sources say

• Not checked yetcites Fabrizio et al., 2004 source
• Not checked yetcites Herker et al., 2004 source

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.”

In 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).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

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).”

What the sources say

• Not checked yetcites Willcox and Willcox, 2014

In the paper

“Features like superoxide levels and regrowth frequency are connected to PCD, an adaptive mechanism required for programmed aging through selective advantage at least in yeast (Fabrizio et al., 2004; Herker et al., 2004).”

What the sources say

• Not checked yetcites Fabrizio et al., 2004 source
• Not checked yetcites Herker et al., 2004 source

In the paper

“Stress-related transcription factors represent the common effectors in yeast, flies, worms, and mammals (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

In the paper

“Moreover, the histone deacetylase SIR2 (the founding member of the sirtuin family) has been linked to CR-mediated anti-aging effects in yeast mother cells, flies, and mammals (Haigis and Guarente, 2006).”

What the sources say

• Not checked yetcites Haigis and Guarente, 2006 source

In the paper

“Interestingly, a recent report showed that mice with transgenic overexpression of fibroblast growth factor 21 (FGF21), a fasting hormone, can extend life span when maintained on an ad libitum diet (Zhang et al., 2012).”

What the sources say

• Not checked yetcites Zhang et al., 2012 source

In the paper

“Strains with dysfunctional PCD have an initial advantage but are eventually overgrown and outcompeted by wild type cells (Fabrizio et al., 2004; Herker et al., 2004).”

What the sources say

• Not checked yetcites Fabrizio et al., 2004 source
• Not checked yetcites Herker et al., 2004 source

In the paper

“Hence, the demise of single individuals in an aged population has a cleaning function that allows only the fittest to survive.”

In the paper

“Importantly, CR-mediated longevity in eukaryotes seems to be governed by a set of conserved nutrient signaling pathways (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

In the paper

“One of the best correlations between CR and improvement in healthspan and prolonged life in humans is the long-lived population in Okinawa, Japan (Mizushima et al., 1997).”

What the sources say

• Not checked yetcites Mizushima et al., 1997 source

In the paper

“Female rats subjected to prolonged CR become infertile in a reversible fashion (Martin et al., 2007), and moderate CR may be harmful to lean human beings (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

In the paper

“Accumulating evidence suggests that protein restriction is necessary and sufficient for depletion of serum IGF1 in humans (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

In the paper

“Many parameters (including husbandry and diet composition) may strongly influence the positive effects of CR.”

In the paper

“Studies with monozygotic twins suggest the accumulation of epigenetic changes as twins age (e.g., demethylation of 5-methylcytosines in DNA), thus affecting the transcriptome (Fraga et al., 2005).”

What the sources say

• Not checked yetcites Fraga et al., 2005 source

In the paper

“Several lines of evidence indicate that fasting regimens exert anti-aging effects.”

In the paper

“It would appear that the high sugar (sucrose) concentration contained in the ad libitum diet (control group) of the UW study (Colman et al., 2009) led to a shortened lifespan within the cohort of control monkeys, thus accounting for the lifespan extension when animals were fed a CR diet.”

What the sources say

• Not checked yetcites Colman et al., 2009 source

In the paper

“Female rats subjected to prolonged CR become infertile in a reversible fashion (Martin et al., 2007), and moderate CR may be harmful to lean human beings (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Martin et al., 2007 source

In the paper

“Indeed, the psychological and physical adversities that accompany a war situation make it difficult to accurately interpret this involuntary restriction of caloric intake.”

In the paper

“Hence, a healthy diet might be comparable to a bad diet (high sugar) plus CR.”

In the paper

“A two-week period of medically supervised, water-only fasting resulted in blood pressure readings below 120/80 mm Hg in 82% of subjects with borderline hypertension (Goldhamer et al., 2002).”

What the sources say

• Not checked yetcites Goldhamer et al., 2002 source

In the paper

“Ten days of water-only fasting normalized blood pressure readings in all hypertensive patients who were taking antihypertensive medication (Goldhamer et al., 2002).”

What the sources say

• Not checked yetcites Goldhamer et al., 2002 source

In the paper

“The single most effective way to lower hypertension is the practice of fasting.”

In the paper

“Such an intermittent fasting strategy may even yield positive effects despite overconsumption of calories.”

In the paper

“Indeed, fasting has been shown to exert a series of beneficial effects on healthspan by minimizing the risk of developing age-related diseases, such as neurodegeneration, cancer, or cardiovascular diseases, in animal models and, possibly, humans (Longo and Mattson, 2014).”

What the sources say

• Not checked yetcites Longo and Mattson, 2014

In the paper

“Fasting cycles have been reported to be as effective as chemotherapy against certain tumors in mice.”

What the sources say

• Not checked yetcites Raffaghello et al., 2008 source

In the paper

“Interestingly, a ketone ester diet, which seemingly recapitulates fasting energy metabolism, alleviates proteopathic and behavioral deficiencies in a mouse model of Alzheimer’s disease (Kashiwaya et al., 2013).”

What the sources say

• Not checked yetcites Kashiwaya et al., 2013 source

In the paper

“When faced with starvation, cancer cells simply die.”

In the paper

“A treatment that combines fasting and chemotherapy rendered 20–60% of mice cancer-free when inoculated with highly aggressive tumors like glioblastoma or pancreatic tumors, which killed 100% of the cohort when treated with chemotherapy alone (Raffaghello et al., 2008).”

What the sources say

• Not checked yetcites Raffaghello et al., 2008 source

In the paper

“However, the BMI is an insufficient indicator of body composition and percent body fat.”

In the paper

“Moreover, alternate day fasting over a period of 2–4 weeks reduces asthma-related symptoms and markers of oxidative stress in overweight people suffering from asthma (Johnson et al., 2007).”

What the sources say

• Not checked yetcites Johnson et al., 2007 source

In the paper

“In rodents as in humans, regular exercise can reduce the risk of morbidity and mortality (Holloszy and Schechtman, 1991; Huffman et al., 2011; Pekkanen et al., 1987; Samorajski et al., 1985).”

What the sources say

• Not checked yetcites Holloszy and Schechtman, 1991
• Not checked yetcites Huffman et al., 2011 source
• Not checked yetcites Pekkanen et al., 1987 source

In the paper

“Several periodic fasting strategies revert features of metabolic syndrome in overweight and obese subjects, which coincide with increases in insulin sensitivity and lipolytic activity (Harvie et al., 2011; Heilbronn et al., 2005; Varady et al., 2009).”

What the sources say

• Not checked yetcites Harvie et al., 2011 source
• Not checked yetcites Heilbronn et al., 2005 source
• Not checked yetcites Varady et al., 2009 source

In the paper

“In line with these observations, it has been demonstrated that fasting facilitates long-term memory formation in Drosophila melanogaster (Hirano et al., 2013).”

What the sources say

• Not checked yetcites Hirano et al., 2013 source

In the paper

“For example, a well-trained athlete may have a BMI equivalent to that of an obese individual because of the athlete’s higher muscle mass density.”

In the paper

“Hence, exercise training can have a beneficial impact against diseases and metabolic disorders that typically accompany aging, notably cardiovascular diseases, diabetes and osteoporosis (Fontana et al., 2010).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

In the paper

“A 3-to-4-month period of CR improves verbal memory in overweight women and aged people (Witte et al., 2009) despite the fact that the brain relies mainly on glucose.”

What the sources say

• Not checked yetcites Witte et al., 2009 source

In the paper

“Marked reduction of metabolic disease markers, such as high blood pressure or levels of circulating IGF1 and C-reactive protein, has been reported in overweight women that were subjected to a 2-day per week fast over 6 months (Harvie et al., 2011).”

What the sources say

• Not checked yetcites Harvie et al., 2011 source

In the paper

“Moreover, the combination of exercise and CR has no additive effect on maximal lifespan in rodents (Holloszy and Schechtman, 1991).”

What the sources say

• Not checked yetcites Holloszy and Schechtman, 1991

In the paper

“Studies on human twins have convincingly demonstrated that adiposity increases the probability of age-related dementia and Alzheimer’s disease (Xu et al., 2011).”

What the sources say

• Not checked yetcites Xu et al., 2011

In the paper

“Contrary to CR, regular exercise fails to extend lifespan (Mercken et al., 2012) despite its clear benefits at improving health-related quality of life.”

What the sources say

• Not checked yetcites Mercken et al., 2012 source

In the paper

“Although virtually all obese people know that stable weight loss would reduce their elevated risk for metabolic diseases and enhance their overall odds for survival, only 20% of overweight individuals are able to lose 10% of their weight for a period of at least 1 year (Wing and Phelan, 2005).”

What the sources say

• Not checked yetcites Wing and Phelan, 2005 source

In the paper

“Of significance, TOR inactivation extends lifespan in yeast (Kaeberlein et al., 2005), flies (Kapahi et al., 2004), worms (Vellai et al., 2003) and mice (Harrison et al., 2009).”

What the sources say

• Not checked yetcites Kaeberlein et al., 2005 source
• Not checked yetcites Kapahi et al., 2004 source
• Not checked yetcites Vellai et al., 2003 source

In the paper

“Mutations that decrease IGF1 levels or activity cause reduced growth and longer life in mice by up to 65% (Coschigano et al., 2000; Holzenberger et al., 2003).”

What the sources say

• Not checked yetcites Coschigano et al., 2000 source
• Not checked yetcites Holzenberger et al., 2003 source

In the paper

“Metformin increases mean and maximum lifespan in different female mouse strains predisposed to high incidence of mammary tumors (Anisimov et al., 2011b; Martin-Montalvo et al., 2013).”

What the sources say

• Not checked yetcites Anisimov et al., 2011b
• Not checked yetcites Martin-Montalvo et al., 2013 source

In the paper

“Because exercise and CR do reveal distinct molecular signatures (Mercken et al., 2013), it is likely that the integration of regular exercise with CR results in synergistic health-promoting effects.”

In the paper

“Middle-aged mice on a diet supplemented with rapamycin survived significantly longer (Harrison et al., 2009); however, reports of the potent immunosuppressive properties of rapamycin suggest that the drug is unsuitable for lifespan extension in humans.”

What the sources say

• Not checked yetcites Harrison et al., 2009 source

In the paper

“Nevertheless, resveratrol offers protection in models of stress- or age-associated diseases, including chronic overfeeding, insulin resistance, type 2 diabetes, or cardiovascular dysfunction (Baur et al., 2006; Lagouge et al., 2006).”

What the sources say

• Not checked yetcites Baur et al., 2006
• Not checked yetcites Lagouge et al., 2006 source

In the paper

“Because exercise and CR do reveal distinct molecular signatures (Mercken et al., 2013), it is likely that the integration of regular exercise with CR results in synergistic health-promoting effects.”

What the sources say

• Not checked yetcites Mercken et al., 2013 source

In the paper

“There are now several reports demonstrating that the effects of metformin on transcription mimic the gene expression profile of animals on CR through the transcriptional regulatory pathways controlling lifespan extension (Anisimov et al., 2011b; Martin-Montalvo et al., 2013).”

What the sources say

• Not checked yetcites Anisimov et al., 2011b
• Not checked yetcites Martin-Montalvo et al., 2013 source

In the paper

“Chronic inhibition of mammalian TOR (mTOR) function by rapamycin promotes insulin resistance and diabetes in laboratory mice (Lamming et al., 2012).”

What the sources say

• Not checked yetcites Lamming et al., 2012 source

In the paper

“Taken together, these results indicate a key modulatory role of mitochondria during aging.”

In the paper

“One can conclude that the anti-aging effects of periodic fasting and treatment with resveratrol, rapamycin or spermidine are based, at least in part, on hormesis.”

In the paper

“Paradoxically, it is the impairment of mitochondrial function and associated lower ATP levels that prolongs lifespan in worms (Dillin et al., 2002; Lee et al., 2003).”

What the sources say

• Not checked yetcites Dillin et al., 2002 source
• Not checked yetcites Lee et al., 2003 source

In the paper

“In recent years, however, fasting and exercise regimens, and a number of small molecules have been shown to prolong life and/or sustain health late in life in model organisms as different as yeast and monkeys.”

In the paper

“In fact, acetyl-CoA controls longevity and autophagy in a panel of model systems (Eisenberg et al., 2014; Mariño et al., 2014): This energy metabolite integrates various nutrition pathways and is the only known donor in acetylation reactions.”

What the sources say

• Not checked yetcites Eisenberg et al., 2014 source
• Not checked yetcites Mariño et al., 2014 source