The Search for Antiaging Interventions: From Elixirs to Fasting Regimens

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.”

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.”

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.”

What the sources say

• Not checked yetcites WHO

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.”

In the paper

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

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.”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

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).”

What the sources say

• Not checked yetcites Anderson et al., 2009 source

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.”

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.”

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).”

What the sources say

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

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).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

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).”

What the sources say

• Not checked yetcites Heilbronn et al., 2005 source

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.”

What the sources say

• Not checked yetcites Johnson et al., 2007 source
• Not checked yetcites Varady et al., 2009 source
• Not checked yetcites Harvie et al., 2011 source

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).”

What the sources say

• Not checked yetcites Colman et al., 2009 source
• Not checked yetcites Mattison et al., 2012 source

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.”

In the paper

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

In the paper

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

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.”

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.”

What the sources say

• Not checked yetcites Colman et al., 2009 source
• Not checked yetcites Mattison et al., 2012 source

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).”

What the sources say

• Not checked yetcites Willcox and Willcox, 2014

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.”

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).”

What the sources say

• Not checked yetcites Mizushima et al., 1997 source

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).”

What the sources say

• Not checked yetcites Mercken et al., 2012 source

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).”

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.”

What the sources say

• Not checked yetcites Mattison et al., 2012 source

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).”

What the sources say

• Not checked yetcites Fontana et al., 2010 source

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.”

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).”

What the sources say

• Not checked yetcites Gurven et al., 2009 source

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).”

What the sources say

• Not checked yetcites Longo and Mattson, 2014

In the paper

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

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).”

What the sources say

• Not checked yetcites Raffaghello et al., 2008 source

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).”

What the sources say

• Not checked yetcites Longo and Mattson, 2014

In the paper

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

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).”

What the sources say

• Not checked yetcites Hatori et al., 2012 source

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.”

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.”

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.”

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).”

What the sources say

• Not checked yetcites Teng et al., 2011 source

In the paper

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

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).”

What the sources say

• Not checked yetcites Flegal et al., 2013 source

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).”

What the sources say

• Not checked yetcites Welborn et al., 2003 source

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.”

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).”

What the sources say

• Not checked yetcites Flegal et al., 2013 source

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.”

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).”

What the sources say

• Not checked yetcites Longo and Mattson, 2014

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).”

What the sources say

• Not checked yetcites Bjedov and Partridge, 2011
• Not checked yetcites Kapahi et al., 2004 source

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).”

What the sources say

• Not checked yetcites Bauer et al., 2004 source
• Not checked yetcites Baur and Sinclair, 2006
• Not checked yetcites Howitz et al., 2003 source

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.”

What the sources say

• Not checked yetcites Baur et al., 2006

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).”

What the sources say

• Not checked yetcites Eisenberg et al., 2009 source

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.”

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.”

What the sources say

• Not checked yetcites Jia and Levine, 2007
• Not checked yetcites Tavernarakis et al., 2008 source

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.”

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).”

What the sources say

• Not checked yetcites Schriner et al., 2005 source

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).”

What the sources say

• Not checked yetcites Pyo et al., 2013 source