Slowing down Aging: Are we ready? (2)

Interventions to Slow Aging in Humans: Are We Ready? (Longo et al., Aging Cell, 2015).

Translated by Evgenia Ryabtseva

(Continuation, the beginning of the article is here.)

The most well-described form of fasting, the effects of which have been analyzed both in rodent experiments and in studies involving humans, is intermittent or alternating fasting, in which feeding for extended periods of time occurs every second day (Trepanowski et al., 2011). Prolonged fasting, in which only water is consumed for at least two consecutive days, is also being actively studied, especially in rodents and lower eukaryotes (Longo & Mattson, 2014). The mechanisms of action of fasting are most well studied in baker's yeast Saccharomyces cerevisiae, in which transfer from a glucose-containing medium to water causes suppression of the activity of signaling pathways mediated by the complexes Tor/S6K and Ras/adenylate cyclase/protein kinase A (PKA), and subsequent activation of stress-resistant transcription factors Msn2/4 and Gis1, regulating a variety of genes performing protective and metabolic functions (Wei et al., 2008). These changes, similar to what is happening in the organisms of starving roundworms and mice, not only provide resistance to a variety of toxins, but also increase life expectancy. In mice, fasting reduces the levels of circulating insulin-like growth factor-1 and causes suppresses the activity of signaling mechanisms mediated by phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT), Tor/S6K and adenylate cyclase/protein kinase A. This, as in the case of yeast, activates many transcription factors, including members of the FOXO or forkhead family (Cheng et al., 2014).

Various types of prolonged or intermittent fasting increase the lifespan of bacteria, roundworms and rodents (Longo & Mattson, 2014). In mouse models, intermittent fasting helps prevent or delay the progression of myocardial infarction, diabetes mellitus, stroke, Alzheimer's and Parkinson's diseases (Longo & Mattson, 2014; Mattson, 2014). Intermittent fasting also protects mice from undesirable side effects of chemotherapy, toxicity mediated by ischemia/reperfusion, and cancer progression, and also stimulates stem cell-dependent regeneration and rejuvenation of the immune system of old animals (Mauro et al., 2014, Safdie et al., 2009, Longo & Mattson 2014 Cheng et al., 2014; Levine et al., 2014). 

Despite the fact that the effect of chronic cycles of intermittent fasting on the duration of a healthy life is unknown, research data indicate that infrequent periods of prolonged fasting, used at intervals once a month or less, can be a powerful inducer of the human body's defense systems and a potential alternative to chronic adherence to a low-calorie diet or intermittent fasting.

Several clinical studies of prolonged and intermittent fasting have already yielded very promising results, indicating that the safety and effectiveness of these interventions are sufficient for conducting long-term clinical studies of their effect on healthy life expectancy (Longo & Mattson, 2014). Preliminary but convincing results of one of the studies indicate that periods of prolonged fasting, followed by a vegetarian diet, suppress inflammation and pain in patients with rheumatoid arthritis (Michalsen et al., 2005). Preliminary results of another study indicate the ability of prolonged fasting to reduce the severity of side effects of chemotherapy in humans (Safdie et al., 2009). Currently, this observation is being tested in several larger randomized clinical trials. In part, the effects of fasting, directed against aging and diseases, may be due to a decrease in the level of insulin-like growth factor-1, glucose and insulin (see the following sections).

The effect of intermittent fasting on human health has been studied more actively than the effect of prolonged fasting. For example, fasting every second day for three weeks reduces body weight, body fat content and insulin concentration in blood plasma in both women and men (Heilbronn et al., 2005), while reducing the caloric content of the diet to 500-600 calories per day for two of the seven days of the week triggers the process burning fat deposits in the abdomen, improves tissue sensitivity to insulin and lowers blood pressure (Harvie et al., 2010).

Prolonged and intermittent fasting causes several undesirable side effects and can be dangerous for people with a very low body mass index, senile elderly people, as well as patients with diabetes mellitus receiving insulin or insulin-like drugs. Therefore, the lack of medical supervision during such interventions can lead to serious consequences. For example, increased tissue sensitivity to insulin during prolonged fasting can lead to severe hypoglycemia and even death in diabetic patients receiving insulin injections. Despite the fact that the main side effects of prolonged and intermittent fasting are very rare and usually reversible, their probability indicates the need to develop, as well as conduct preclinical and clinical studies of diets, the effect of which is comparable to the results of fasting or even exceeds them while minimizing the likelihood of undesirable side effects.

Calorie restriction due to proteins contributes to the positive effect of a low-calorie diet on the life expectancy of animals (Gallinetti et al., 2013; Mirzaei et al., 2014). Limiting the use of certain essential amino acids, including methionine and tryptophan, can also increase life expectancy (Spindler, 2009). However, it is not known whether the mechanisms underlying this effect overlap with the mechanisms of action of other low-calorie diet regimens. It is also unknown whether the effects of limiting the use of various essential amino acids are specific.

Amino acid levels are determined by at least two mechanisms preserved in the process of evolution, one of which involves a general control kinase with constant repression-2 (GCN2), and the other – mTOR. In mammals, mTOR is activated by amino acids, especially leucine, whereas GCN2 is activated by the absence of many individual amino acids. The defense mechanisms that turn on after GCN2 activation and suppression of mTOR activity in conditions of protein/amino acid deficiency are mostly unclear. However, it is known that GCN2 activation stabilizes the transcription factor ATF4, which can be a key mediator of various models of increased lifespan, including models of pituitary dwarfism and methionine restriction (Li et al., 2014).

The main factor determining the effect of limiting protein intake on life expectancy in many species is the ratio between the amount of protein and other sources of calories (carbohydrates, fats), the effect of which on the aging process is most likely partly due to the effect on the signaling mechanism mediated by mTORC1 (Solon-Biet et al., 2014). GCN2 is necessary to increase the lifespan of yeast with methionine restriction (Wu et al., 2013), but other mechanisms, including autophagy (Ruckenstuhl et al., 2014) and retrograde activation of signaling pathways in mitochondria (Johnson & Johnson, 2014), also play certain roles. Serine, threonine, and valine deficiency increases yeast lifespan through mechanisms implying suppression of the activity of mammalian protein orthologs such as phosphatidylinositol-dependent kinase (PDK) and Tor/S6K (Mirisola, et al., 2014). 

Reducing the amount of methionine in the diet also increases the life expectancy of fruit flies, but the underlying mechanism of this phenomenon is generally unclear (Lee et al., 2014). It has been shown that in mice, the amount of methionine ingested from food is determined by a growth hormone-mediated signaling mechanism (Brown-Borg et al. 2014). In the case of rodents, limiting the amount of proteins/amino acids also has a positive effect on health in models of acute stress and chronic diseases. The absence of tryptophan in the feed during the week increases the resistance of the liver and kidneys to acute stress caused by ischemia/reperfusion, and the main role in this belongs to GCN2 (Peng et al., 2012). However, under conditions of general protein starvation, GCN2 loses its main role in the positive effect. The key mechanism of stress resistance in this case is the suppression of mTORC1 activity. This effect may be partly mediated by the negative effect of mTORC1 on tissue sensitivity to insulin. In other words, suppression of its activity provides an opportunity to enhance survival-promoting signals after reperfusion (Harputlugil et al., 2014).

The positive effects of short-term protein starvation also include the prevention of intimal hyperplasia (Mauro et al., 2014). Similarly, weekly cycles of protein starvation alternating with weekly cycles of unrestricted access to a full diet prevent the phosphorylation of Tau protein in a mouse model of Alzheimer's disease (Parrella et al., 2013). Finally, protein starvation has a positive effect on metabolism, activating a reaction similar to the reaction to starvation, involving both GCN2 and the receptor activated by the proliferator peroxis-alpha (PPAR-alpha), as well as causing an increase in the level of the fasting hormone – fibroblast growth factor-21 (FGF21) (Laeger et al., 2014).

To date, a very small number of clinical studies have been conducted to study the potentially positive effects of protein and/or amino acid starvation on aging and the development of chronic age-related diseases (Cavuoto & Fenech, 2012; Mirzaei et al., 2014). According to the results of studies on mice (Solon-Biet et al., 2014), the lowest protein intake was associated with a reduced risk of cancer and overall mortality, but only in the group of people aged 65 years and younger (Levine et al., 2014). Due to inefficient protein utilization associated with differences in protein quality (the content of essential amino acids and digestibility), the recommended minimum amount of protein of 0.66 g/kg of body weight per day for men and women over 18 years of age is likely higher for older people than for young adults (Levine et al., 2014).

Continuation: pharmacological interventions reproducing the effects of a low-calorie diet.

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27.08.2015