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mTORC1 and Nutritional Interventions in Ageing: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Reinald Pamplona.

The effect of mTOR complex 1 (mTORC1) inhibitors in ageing has been a matter of scientific study since the 1990s. In fact, most initial efforts elucidating the beneficial effects of rapamycin have revealed its role in ageing, with Romero et al. describing in 1995 its effect in preventing reduced bone growth in aged rat. Since mTORC1 responds to nutritional availability, the effects of mTORC1 inhibition using specific inhibitors such as rapamycin or through nutritional interventions in ageing and health have been widely reviewed.

  • mTORC1
  • ageing
  • Calorie restriction

1. Rapamycin Treatment

Short-term rapamycin treatment is enough to reduce mechanistic target of rapamycin (mTOR) content and signalling in multiple tissues, including heart, kidney, liver, intestine, and visceral fat [36,50,51][1][2][3] and signalling [52,53][4][5]. Remarkably, when injected intraperitoneally, reduced organismal mTOR signalling has been reported after only 1 h [53][5]. The reduced mTOR activity occurs along with an enhanced longevity [36,50,51,53,54,55,56][1][2][3][5][6][7][8]. Interestingly, rapamycin reduces mTOR activity and increases longevity in a dose-dependent manner [50][2] (Table 41).
In old rodents, short-term rapamycin intake is enough to significantly increase longevity [57,58][9][10] and reduce mortality [38][11]. The health span is also improved, as it is associated with delayed ageing [36,58][1][10], increased global activity [56][8], reduced tumour incidence [56][8], and enhanced immunity [37][12]. Additionally, decline in muscular function and motor coordination [58][10] and hematopoietic stem cell function [37][12] with age are preserved.
The molecular mechanisms through which rapamycin extends longevity and delays ageing are diverse, and include reduced ROS production at complex I, protein and lipid oxidation, and mitochondrial DNA alteration, along with enhanced mitochondrial biogenesis, stress resistance, autophagy and modulation of lipid metabolism [36,50,51,54,55][1][2][3][6][7]. The effects on protein translation and chromatin structure are complex. Intuitively, mTOR complex 1 (mTORC1) inhibition should lead to a translation repression [59][13], as has been reported [50][2]. However, a recent study revealed that rapamycin induces histone expression in the intestine of female flies [51][3]. Accordingly, previous studies have already described the existence of non-canonical mechanisms of protein synthesis mediated though eIF3, an mTOR downstream effector, which remains to be completely elucidated [60,61][14][15]. Hence, these data point to a complex mechanism through which mTORC1 could lead to the synthesis of specific proteins such as histones, altering chromatin and repressing global translation, thus saving energy under starving conditions.
Interestingly, most of the rapamycin-mediated effects on health and longevity are sex dependent. In fact, mTOR signalling is globally depleted in females after treatment, whereas it was only reduced in males [53][5]. Accordingly, most studies reported that the lifespan extension effect is higher in female compared to male [50[2][8],56], even when applied at old ages [52,57][4][9].
Females also seem to be more sensitive to the adverse effects of rapamycin, which are dependent on administration patterns, specifically high dosage and long periods. Accordingly, dosage of rapamycin (8 mg/kg intraperitoneally [58][10] or 1.5 mg/kg subcutaneously [62][16]) is associated with higher incidence of chromosome aberration in bone marrow cells, and higher cancer incidence and invasiveness. The effects of a high dosage of rapamycin are unclear, as short-term treatment did not alter longevity [58][10], although high-dose administration throughout the lifetime, starting at young age, extended longevity [62][16]. Moderate rapamycin treatment for 1000 d is associated with a higher incidence of cancer (64% as a cause of death) compared to controls (46%) [52][4]. Interestingly, and probably associated with the previously mentioned chromosome aberration [58][10], the most prevalent carcinoma was lymphoma [56,62][8][16].
These protocols might lead to altered plasma rapamycin levels. In fact, although not significant, two studies have reported that slightly lower rapamycin plasma levels is associated with higher longevity [52[4][10],58], even when mTOR signalling is significantly lowered [52][4], and independently of sex. These results suggest that it might be worth deeply studying rapamycin metabolism and the association between its plasma levels and its effects on health. Nonetheless, more studies are needed to elucidate the appropriate administration pattern and dosage, as has been described previously [63,64][17][18].
Table 41. mTOR regulation through rapamycin. Increased or reduced mTOR content can refer to either transcript content gene expression, protein content, protein phosphorylation or activity after insulin stimulation. Letters refer to: maximum longevity (ML), in years; female (F); male (M); not determined (n.d.). Nutritional intervention (NI) duration is grouped according to different time periods: 1 very short-term (hours to days); 2 short-term (1 to 6 months); 3 long-term (more than 6 months); 4 lifetime (to natural death of the specimen). The beginning of the NI on is defined by superscript letters: A NI applied to young specimens; B NI applied to adult specimens; C NI applied to middle-aged specimens; D NI applied to old specimens. Symbols refer to: * Studies in which the expression, content or phosphorylation of mTORC1 itself were evaluated; # Studies in which mTORC1 itself was not evaluated, but its upstream or downstream effectors were.
Species Sex Intervention mTORC1 Tissue Phenotype Longevity Ref.
Worm - Rapamycin A Reduced * Whole n.d. +21% [55][7]
Fly M/F Rapamycin D Reduced # Whole, abdomen,

thorax and head		 n.d. B1+18% [50][2]
Reduced * Liver n.d. n.d. [73][27] Fly F Rapamycin D Reduced # Intestine n.d. +8% [51]
Human[3]
F CR (−1000 kcal) B3 Reduced Amygdala Improved function

and metabolic health		 n.d. [77][31] Fly M/F Rapamycin D Reduced n.d. n.d. +33% [54][6]
Rat F CR (40%) B3 Reduced * Skeletal muscle Delayed

ageing		 n.d. [38][11] Mouse M/F Rapamycin A2 Reduced # Heart, liver, kidney

and intestine		 n.d. n.d. [
Humans53][5]
F/M CR (30%) B4 Reduced - Improved memory

and metabolic health		 n.d. [79][33] Mouse M Rapamycin B3 Reduced # Liver Delayed ageing n.d. [36][1]
Mouse M CR (30%) C1 Reduced * Hippocampus

(neurons)		 n.d. n.d. [69][23] Mouse F Rapamycin B4 Reduced n.d. n.d. +4% [57][9]
Mouse
Mouse M CR (30%) C1 Reduced * Hippocampus

(neurons)		 Improved learning

and memory		 n.d. [70][24] M Rapamycin B4 Reduced n.d. n.d. +5% [57][9]
Mouse F
Mouse M CR (30%) C1 Reduced * Hippocampus

(astrocytes)		 n.d. n.d. [71][25] Rapamycin B4 Reduced n.d. Delayed ageing +9–14% [58][10]
Mouse M Rapamycin B4 Reduced n.d. Delayed ageing +14% [58][10]
Mouse M Rapamycin B4 Reduced * n.d. n.d. +60% [37][12]
Mouse F Rapamycin D1 Reduced n.d. Reduced cancer +9% [62][16]
Mouse F Rapamycin D2 Reduced n.d. n.d. +9–15% [56][8]
Mouse M Rapamycin D2 Reduced n.d. n.d. +15–18% [56][8]
Mouse F Rapamycin C2/D4 Reduced # Visceral fat n.d. +14% [52][4]
Mouse M Rapamycin C2/D4 Reduced # Visceral fat n.d. +9% [52][4]
Mouse F Rapamycin D4 Reduced n.d. n.d. +12% [57][9]
Mouse M Rapamycin D4 Reduced n.d. n.d. +9% [57][9]

2. Calorie and Amino Acid Restriction

Calorie restriction (CR) is defined as a reduced calorie intake without inducing malnutrition. It is widely accepted that CR is the only nutritional intervention capable of robustly extending longevity in animal models and promoting health span. Additionally, it has been elucidated that most of these effects are due to the specific restriction of calories from protein intake [65][19], rather than those from lipids [66][20] or carbohydrates [67][21]. Accordingly, isocaloric protein restriction (PR) is responsible for most of these effects [68][22]. Among all the amino acids constituting proteins in living beings, it has been demonstrated that the selected isocaloric restriction of sulphur containing the amino acid methionine (MetR) accounts for most, if not all, of the beneficial effects attributed to CR and PR [68][22].
Not surprisingly, CR, PR and MetR prevent mTOR signalling activation, by either regulating mTOR content [69,70,71][23][24][25] and its phosphorylation [38[11][23][24][25][26][27],69,70,71,72,73], its downstream effector S6K [38,72[11][26][27][28],73,74], or its upstream regulator TSC [73][27] (Table 52). The regulation of mTOR signalling is complex, since while mTOR phosphorylation is dose dependent below 5% to 40%CR regimens [73][27], S6K and TSC regulation is dual. In fact, 5%CR is enough to reduce S6K phosphorylation, although more intense CR (40%) is needed to reduce TSC phosphorylation. In old specimens, 40%CR [38][11] or 80%MetR [75][29] are sufficient to lower mTOR signalling and to restore it to the basal levels of activation found in young specimens, delaying ageing [38][11].
CR, PR and MetR promote health span at organismal levels, including reduced body weight and percentage of fat mass, lower blood glucose and insulin, and lower plasma TG and cholesterol [72[26][29][30][31],75,76,77], suggesting improved metabolic health. Learning and memory processes are also improved [70,71[24][25][31][32][33],77,78,79], and tumour incidence is reduced [80][34]. At the molecular level, the intracellular processes regulated by mTOR upon restrictions include increased ROS and NRF2 target genes to maintain proper hormesis, increased expression of genes related to fatty acid oxidation peroxisome β-oxidation, as well as pro-apoptotic genes and reduced neuroinflammation [71,74,76,78][25][28][30][32].
Ageing leads to sarcopenia, which is regulated though mTORC1, as described previously. Among all the organismal effects, 40%CR in skeletal muscle from middle aged specimens led to mTORC1 inhibition and reduced protein degradation, contributing to limiting age-related sarcopenia [74][28]. However, DR [76][30] and PR [74][28] also led to reduced plasma and hepatic content of Met, which is essential for starting protein synthesis in eukaryotes and could affect muscle maintenance during ageing. Recently, it was described that the initial sensing of MetR occurs in the liver, where a stress response for reducing Met use and protein synthesis is activated [81][35]. These molecular processes depend upon mTOR, and are directed to restore basal Met levels after 4 days, hence making it possible to maintain proper protein synthesis.
The production of ROS, and the accumulation of oxidized biomolecules constitutes one of the main causes of ageing. Recently, it has been reported that CR and MetR benefits, in terms of oxidative damage, depend on sulphur disulphide (H2S) production [75,76][29][30]. This molecule is a by-product of the transulphuration pathway (TSP), which relates two sulphur-containing amino acids, such as Met and cysteine. In rodents undergoing CR and MetR, tissue TSP intermediates are reduced, along with an enhanced content of TSP-related enzymes and H2S levels [75,76][29][30]. Consequently, tissue damage is lowered. Additionally, when mTORC1 is constitutively active, H2S production is depleted, and Met levels are reduced but maintained at a higher level than that of the control [76][30]. Evidence also points to H2S as a neuroprotective factor for preventing the development of neurodegenerative diseases [78][32]. Taken together, these data make it possible to establish a relationship between CR, Met and mTOR signalling. Supporting this data, Gu and collaborators described the existence of SAMTOR, a protein that inhibits mTOR after sensing nutrient availability via SAM, a metabolite derived from methionine [82][36].
Branched-chain amino acids (BCAA) are amino acids with an aliphatic side-chain, and include leucine (Leu), isoleucine (Ile) and valine (Val). Recently, the restriction of BCAA (BCAAR) has been found to be associated with improved health span and longevity, although most of these effects are sex dependent [39][37]. Although BCAAR improves metabolic health in both young and old male and female mice, most of the beneficial effects are limited to males. Accordingly, lifespan is increased and frailty is reduced in aged specimens, along with a reduction in mTOR signalling. Conversely, in females, mTOR signalling is unaffected, and it is associated with higher early mortality. Accordingly, BCAA supplementation shortens lifespan and worsens metabolic health, although these processes seem to be independent of mTOR [83][38]. In humans, supplementation with BCAA is neurotoxic, and promote oxidative stress and inflammation in peripheral blood mononuclear cells through mTORC1 activation [84][39].
Although the mechanisms through BCAA extend their effects, Leu depletion leads to improved metabolic health and reduced mTOR phosphorylation and signalling [72,85][26][40]. Restriction of Leu (LeuR) and MetR act through similar pathways, since some of the beneficial effects induced by MetR can also be observed under LeuR [72][26]. However, MetR emerges as the most robust intervention, as it induces more intense effects.
Table 52. mTOR regulation through nutritional interventions. Increased or reduced mTOR content can refer to transcript content, gene expression, protein content, protein phosphorylation or activity after insulin stimulation. Letters refer to: maximum longevity (ML), in years; dietary restriction (DR); protein restriction (PR); branched-chain amino acids restriction (BCAAR); leucine restriction (LeuR); methionine restriction (MetR); female (f); male (m); not determined (n.d.). Nutritional intervention (NI) duration is grouped according to different time periods: 1 very short-term (hours to days); 2 short-term (1 to 6 months); 3 long-term (more than 6 months); 4 lifetime (to natural death of the specimen). Beginning of the NI on is defined by superscript letters: A NI applied to young specimens; B NI applied to adult specimens; C NI applied to middle-aged specimens; D NI applied to old specimens. Symbols refer to: * Studies in which the expression, content or phosphorylation of mTORC1 itself were evaluated; # Studies in which mTORC1 itself wasn’t evaluated, but its upstream or downstream effectors were.
Species Sex Intensity mTORC1 Tissue Phenotype Longevity Ref.
Mouse M/F CR (50%) A1 Reduced - n.d. n.d. [76][30]
Rat F CR (40%)
Mouse
F
PR (100%)
A1 Reduced # Liver n.d. n.d. [74][28]
Mouse F PR (7–21%) D1 Reduced # Liver, heart

skeletal muscle,

adipose tissue		 n.d. n.d. [80][34]
Mouse F MetR (80%) B1 Reduced Hippocampus,

cortex		 Improved learning

and memory		 n.d. [78][32]
Mouse M MetR (80%) B2 Reduced * Liver Improved

metabolic health		 n.d. [72][26]
Mouse M MetR (80%) B4 Reduced * Kidney Delayed

ageing		 n.d. [75][29]
Mouse M/F MetR (80%) D1 Reduced * n.d. n.d. +25% [75][29]
Mouse M BCAAR (70%) C1/C3/D1 Reduced Heart, liver Delayed ageing +12.3 [39][37]
Mouse F BCAAR (70%) D1/D3 Reduced n.d. Improved

metabolic health		 n.d. [39][37]
Mouse M LeuR (80%) B2 Reduced * Liver n.d. n.d. [72][26]
Mouse M LeuR (0%) B2 Reduced * Liver n.d. n.d. [85][40]

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