Aging, Healthspan, Lifespan, and Longevity 3.01

3.01 Protein consumption and aging.

This may be the biggest surprise. Protein is widely considered to be one of the most important nutrients and the popular press emphasizes the importance of getting enough protein. The popularity of high protein diets for weight loss adds to this belief in the benefits of protein. Of course, proteins are the necessary building blocks of the body, but the question we are asking here is how much protein in the diet provides the maximum healthspan and lifespan?

Here are some interesting studies:
Age (Dordr). 2012 Dec;34(6):1361-8. doi: 10.1007/s11357-011-9308-3. Epub 2011 Sep 9.
Protein:carbohydrate ratios explain life span patterns found in Queensland fruit fly on diets varying in yeast:sugar ratios.
Fanson BG1, Taylor PW.
"Abstract
Dietary restriction extends life span across a vast diversity of taxa, but significant challenges remain in elucidating the underlying mechanisms. Distinguishing between caloric and nutrient effects is an essential step. Recent studies with Drosophila and tephritid fruit flies have reported increased life span as dietary yeast-to-sugar ratios decreased and these effects have been attributed to changes in protein-to-carbohydrate (P:C) ratios of the diets rather than calories.
... female Queensland fruit flies (Q-flies) were fed 1 of 18 diets varying in P:C ratios and diet concentration. Diet consumption, egg production, and life span were recorded for each fly. In close concordance with recent studies using yeast diets, flies had increased life span as P:C ratios decreased, and caloric restriction did not extend life span. ...Our results substantiate recent claims that P:C ratios significantly modulate life span in flies."

So in flies, lower protein increases lifespan. Here is another study below with the same results in crickets, fruit flies and mice:

J Endocrinol. 2015 Jul; 226(1): R17–R28.

Macronutrients and caloric intake in health and longevity

Stephen J. Simpson
"In the field cricket Teleogryllus commodus and fruit fly Drosophila melanogaster, the macronutrient blend that maximized lifespan was markedly different from diets which maximized reproductive variables (Jensen et al. 2015; Maklakov, et al. 2008). Maximal longevity occurred on low protein (P), high carbohydrate (C) diets in both males and females, while a higher P:C ratio was better for reproduction in females only. Consuming a low proportion of protein in the diet relative to carbohydrate, not total calories, extended lifespan in ad libitum-fed flies (Bruce, et al. 2013; Lee et al. 2008), while diets with a higher proportion of protein shortened lifespan but improved reproduction (Lee et al. 2008). This result has been replicated in several other insect species (Dussutour and Simpson 2009; Fanson, et al. 2009; Grandison, et al. 2009; Lee et al. 2008; Piper et al. 2011) and consistently indicates that the balance of macronutrients is the chief nutritional cue that directs metabolism towards longevity or reproduction (Wilder, et al. 2012). A recent study in mice showed that ad libitum low protein, high carbohydrate diets fed short-term improved several markers of health including insulin, HOMA, glucose tolerance and triglycerides to a level comparable to CR, but without at 40% reduction in total calorie intake (Solon-Biet, et al. 2015a). Long-term investigations in ad libitum-fed mice across 25 different diets varying in macronutrient composition support these findings, showing that latelife health and longevity were optimized not by reducing energy intake, but by low P:C diets (Solon-Biet et al. 2014). In an attempt to stabilize protein intake, mice displayed a compensatory increase in food intake on low protein diets, resulting in increased energy intake and greater adiposity, but experienced a significant increase in lifespan, improved blood pressure, lipid profiles, mitochondrial function, insulin sensitivity (Solon-Biet et al. 2014) and immune function (T and B cell populations) measured at 15 months (Le Couteur, et al."

Here's more on rodents and humans:

Trends Endocrinol Metab. 2014 Nov;25(11):558-66. doi: 10.1016/j.tem.2014.07.002. Epub 2014 Aug 19.

Protein and amino acid restriction, aging and disease: from yeast to humans.

Mirzaei H1, Suarez JA1, Longo VD2.
"Abstract
Many of the effects of dietary restriction (DR) on longevity and health span in model organisms have been linked to reduced protein and amino acid (AA) intake and the stimulation of specific nutrient signaling pathways. Studies in yeast have shown that addition of serine, threonine, and valine in media promotes cellular sensitization and aging by activating different but connected pathways. Protein or essential AA restriction extends both lifespan and healthspan in rodent models. In humans, protein restriction (PR) has been associated with reduced cancer, diabetes, and overall mortality. Thus, interventions aimed at lowering the intake of proteins or specific AAs can be beneficial and have the potential to be widely adopted and effective in optimizing healthspan.

Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):74-9. doi: 10.1097/MCO.0000000000000239.

The conserved role of protein restriction in aging and disease.

Mirzaei H1, Raynes R, Longo VD.
"Abstract
PURPOSE OF REVIEW:
Dietary interventions are effective strategies for preventing disease and promoting health span. Many of the effects of dietary restriction are linked to amino acid and protein levels and their regulation of nutrient-signaling pathways. Thus, protein restriction is a promising therapeutic strategy for preventing aging-related diseases and extending life span.
RECENT FINDINGS:
Studies in yeast and flies have shown that amino acid restriction promotes longevity and protection. In rodents, protein restriction extends life span and alleviates detrimental aging phenotypes. Finally, clinical trials in middle-aged adults have demonstrated the role of a protein-restricted diet in promoting health span. Interestingly, the population over the age of 65 may not benefit from severe protein restriction potentially because of the increased physiological decline that leads to decreased amino acid absorption and altered protein synthesis."

Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model.

Fontana L6,10,11.
"The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumors
Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. ...Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases."

Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR.

Mitchell JR.
Department of Genetics and Complex Diseases, Harvard School of Public Health,
"Abstract
DR (dietary restriction), or reduced food intake without malnutrition, is associated with extended longevity, improved metabolic fitness and increased stress resistance in a wide range of organisms. DR is often referred to as calorie restriction, implying that reduced energy intake is responsible for its widespread and evolutionarily conserved benefits. However, recent data indicate dietary amino acid restriction as a key mediator of DR benefits. In fruitflies, an imbalance in essential amino acid intake is thought to underlie longevity benefits of DR. In mammals, reduced dietary protein or essential amino acid intake can extend longevity, improve metabolic fitness and increase stress resistance. In the present paper we review two evolutionarily conserved signal transduction pathways responsible for sensing amino acid levels. The eIF2α (eukaryotic initiation factor 2α) kinase GCN2 (general amino acid control non-derepressible 2) ...These two signal transduction pathways react to amino acid deprivation by inhibiting general protein translation while at the same time increasing translation of specific mRNAs involved in restoring homoeostasis. Together, these pathways may contribute to the regulation of longevity, metabolic fitness and stress resistance."

J Clin Invest. 2014 Sep 2; 124(9): 3913–3922.

FGF21 is an endocrine signal of protein restriction

Christopher D. Morrison1
"Discussion
FGF21 has received considerable attention due to its potent antidiabetic effects in rodent models, yet little is known regarding its physiological role. Previous work has implicated FGF21 in the metabolic response to starvation and a KD in rodent models (6, 7, 34). Here, we provide evidence that the induction of FGF21 during starvation and KD is mediated primarily by reduced protein intake, with protein restriction producing a robust increase in circulating FGF21 in both rodents and humans."

FGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects. KD is ketogenic diet. The above paper says the benefits of a KD diet are due to protein restriction not carbohydrate restriction as is popularly believed.

A provegetarian food pattern and reduction in total mortality in the Prevención con Dieta Mediterránea

Ramon Estruch
"Abstract
Background: Vegetarian diets have been associated with reduced mortality. Because a pure vegetarian diet might not easily be embraced by many individuals, consuming preferentially plant-derived foods would be a more easily understood message. A provegetarian food pattern (FP) emphasizing preference for plant-derived foods might reduce all-cause mortality.
Objective: The objective was to identify the association between an a priori–defined provegetarian FP and all-cause mortality.
Design: We followed 7216 participants (57% women; mean age: 67 y) at high cardiovascular risk for a median of 4.8 y. A validated 137-item semiquantitative food-frequency questionnaire was administered at baseline and yearly thereafter. Fruit, vegetables, nuts, cereals, legumes, olive oil, and potatoes were positively weighted. Added animal fats, eggs, fish, dairy products, and meats or meat products were negatively weighted. Energy-adjusted quintiles were used to assign points to build the provegetarian FP (range: 12–60 points). Deaths were confirmed by review of medical records and the National Death Index.
Results: There were 323 deaths during the follow-up period (76 from cardiovascular causes, 130 from cancer, 117 for noncancer, noncardiovascular causes). Higher baseline conformity with the provegetarian FP was associated with lower mortality (multivariable-adjusted HR for ≥40 compared with <30 points: 0.59; 95% CI: 0.40, 0.88). Similar results were found with the use of updated information on diet (RR: 0.59; 95% CI: 0.39, 0.89).
Conclusions: Among omnivorous subjects at high cardiovascular risk, better conformity with an FP that emphasized plant-derived foods was associated with a reduced risk of all-cause mortality. This trial was registered at www.controlled-trials.com as ISRCTN35739639.

Vegetarian diets are naturally low in protein and vegan diets are more substantially lower in protein.

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans

John O. Holloszy1,2
"Summary
Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg −1 of body weight per day to 0.95 g kg −1 of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL −1 to 152 ng mL −1 . These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions."

Meat and cheese may be as bad for you as smoking

March 4, 2014 University of Southern California
"Summary:
A high-protein diet during middle age makes you nearly twice as likely to die and four times more likely to die of cancer, but moderate protein intake is good for you after 65. But how much protein we should eat has long been a controversial topic -- muddled by the popularity of protein-heavy diets such as Paleo and Atkins. Before this study, researchers had never shown a definitive correlation between high protein consumption and mortality risk.
Not only is excessive protein consumption linked to a dramatic rise in cancer mortality, but middle-aged people who eat lots of proteins from animal sources -- including meat, milk and cheese -- are also more susceptible to early death in general, according to new research.... Protein-lovers were 74 percent more likely to die of any cause within the study period than their more low-protein counterparts."

GCN2 and TOR converge on aging

Syntichaki
"In response to amino acid deprivation GCN2 is activated, upon binding of uncharged tRNAs, whereas TOR is inhibited through regulation of its localization. ...These effects might be also responsible for lifespan extension through down-regulation of mRNA translation. Inhibition of TOR signaling, by genetic or pharmacological means, has been associated with treatment of several diseases and increased lifespan in many organisms, including humans [3]."

Age Ageing. 2016 Jul;45(4):443-7. doi: 10.1093/ageing/afw069. Epub 2016 Apr 28.

New Horizons: Dietary protein, ageing and the Okinawan ratio.

Simpson SJ2.
"Abstract
Nutrition has profound effects on ageing and lifespan. Caloric restriction is the major nutritional intervention that historically has been shown to influence lifespan and/or healthspan in many animal models. Studies have suggested that a reduction in protein intake can also increase lifespan, albeit not as dramatically as caloric restriction. More recent research based on nutritional geometry has attempted to define the effects of nutrition on ageing over a broad landscape of dietary macronutrients and energy content. Such studies in insects and mice indicate that animals with ad libitum access to low-protein, high-carbohydrate diets have longest lifespans. Remarkably, the optimum content and ratio of dietary protein to carbohydrates for ageing in experimental animals are almost identical to those in the traditional diets of the long-lived people on the island of Okinawa."

Does low meat consumption increase life expectancy in humans?

Gary E Fraser
From the Departments of Epidemiology & Biostatistics (PNS, JS, and GEF) and Nutrition (JS), School of Public Health, Loma Linda University, Loma Linda.
"Abstract
Background: Since meat products represent a major source of protein in the Western diet, findings on whether meat intake significantly contributes to the burden of fatal disease have important clinical and public health implications.
Objective: The objective was to examine whether a very low meat intake (less than weekly) contributes to greater longevity.
Design: We reviewed data from 6 prospective cohort studies and report new findings on the life expectancy of long-term vegetarians from the Adventist Health Study.
Results: Our review of the 6 studies found the following trends: 1) a very low meat intake was associated with a significant decrease in risk of death in 4 studies, a nonsignificant decrease in risk of death in the fifth study, and virtually no association in the sixth study; 2) 2 of the studies in which a low meat intake significantly decreased mortality risk also indicated that a longer duration (≥ 2 decades) of adherence to this diet contributed to a significant decrease in mortality risk and a significant 3.6-y (95% CI: 1.4, 5.8 y) increase in life expectancy; and 3) the protective effect of a very low meat intake seems to attenuate after the ninth decade. Some of the variation in the survival advantage in vegetarians may have been due to marked differences between studies in adjustment for confounders, the definition of vegetarian, measurement error, age distribution, the healthy volunteer effect, and intake of specific plant foods by the vegetarians.
Conclusion: Current prospective cohort data from adults in North America and Europe raise the possibility that a lifestyle pattern that includes a very low meat intake is associated with greater longevity."

**Conclusions on increasing our longevity so far:
1.01 Caloric Restriction
2.01 Intermittent Fasting
3.01 Protein restriction: adopting a plant based diet is a natural way to reduce protein consumption. At least 5- 6% protein is required for health so one should not eliminate all protein. A varied vegan diet provides 10-12% protein which matches the protein levels in the studies that increases health and longevity. A nutrient tracking app can be used to see where your protein consumption levels are. I have found that it is very difficult to consume under 10% protein if beans, grains or nuts are consumed. Vegans who limit their diet further to only fruit, or include no grains, beans or nuts will probably be protein deficient.

Next we will discover another way to get the same results - follow me to check it out! There are many more ways coming to increase your healthspan and lifespan.**