>>Non direi:
Si, intedevo una tua opinione supportata da quello che puoi avere letto in rete, anche attigendo ad articoli specialistici. Le interpretazioni sono state diverse ma l'unica che ha prodotto risultati che erano stati previsti (anche se con un dosaggio di rapamicina proporzionalmnte 60 volte superiore rispetto alla dose somministrata a coloro che hanno un organo trapiantato) è stata la teoria mTOR centrica. Diciamo che a me non interessa tanto l'auctoritas che sta dietro a certe affermazioni, ma il rigore logico che collega le varie argomentazioni. In base a tale rigore logico credo che la mTOR centric theory sia la migliore fra le spiegazioni sugli effetti della CR. Se è vera sarà possibile evitare di vivere come gli anacoreti beneficiando al contempo di una speranza di vita più lunga e più sana.
un estratto
The ROS theory must explain why the germ line is immortal, while the soma is mortal. Why free radicals do not damage the germ line? It was suggested that, although cells can repair damage completely, only germ/stem cells actually need to do that. If an organism (the soma) dies from external causes (predators, starvation, infections and so on), then there is no need to be immortal. It was suggested that somatic repair is limited by energetic resources that are allocated for growth and reproduction. 49 This is logical. Yet, if an anti-aging repair (and therefore life span) were limited by resources (food), then an increase in food intake would extend life span. This is exactly the opposite of what is observed: unrestricted calorie consumption accelerates aging, whereas calorie restriction (CR) extends life span. To solve the problem it was postulated that the organism acquires a hypothetical state of repair, exactly when resources are limited. 49 According to this point of view, animals allocate resources for anti-aging repair in order to live longer.49 This leads to several contradictions as discussed next. In the wild, living beings predominantly die from external causes (predators, starvation, cold and infections) and therefore aging does not limit life span in the wild. This explains aging from evolutionary perspective.50,51 Yet, as we just discussed, according to the allocation model, during starvation the organism re-allocates resources to antiaging repair in order to live longer. While becoming long-lived, it can reproduce later (when the famine is over). This implies that aging limits both life span and reproduction in the wild. This cannot be reconciled with the evolutionary theory of aging
Ma già avevo postato i limiti di questo approccio:
To defend the allocation model, it was suggested that, while shutting down reproduction, food shortage improves repair (Fig. 1B). Inhibition of aging will extend potential life span and will allow the organism to reproduce later, when the famine is over. Delayed aging represents “a strategy to cope with periods of famine”.2 This is paradoxical. Let us consider an analogy. Imagine you divide your salary to pay for your apartment and other needs. If you were fired from your job, would you move to a luxurious apartment, while giving up other needs altogether? On the contrary, you probably would consider a less expensive apartment. Similarly, increased antiaging repair (in order to slow aging) is a luxury, especially during periods of famine. In contrast, a sensible biological strategy would be to shut down antiaging repair and to allocate all resources for immediate needs and reproduction.
For example, the anti-diabetic drug metformin, which extends lifespan in rodents,63 inhibits the TOR pathway. Also, caloric restriction (CR) extends lifespan in almost all species from yeast to mice. And this fits the TOR-centric model naturally. Indeed, nutrients activate the nutrient-sensing TOR pathway by definition, and lack of nutrients deactivates it. In humans, it has been shown that nutrients activate TOR in the muscle tissue, causing insulin resistance. This effect was blocked by rapamycin.64 Evidence emerges that CR slows down aging via the TOR pathway in yeast, C. elegans and Drosophila.60,62,65,66 Finally, the TOR pathway is involved in diseases such as cancers, type II diabetes and its complications (retinopathy and renal hypertrophy), age-related macular degeneration, obesity, atherosclerosis, cardiac hypertrophy, aortic aneurysm osteoporosis, organ fibrosis (liver, renal and cardiac fibrosis), neurodegeneration, Alzheimer’s and Parkinson’s diseases, psoriasis, skin scars, keloids and arthritis. 2,67-69 And diseases of aging limit our lifespan. How does TOR cause aging? The notion that aging is the accumulation of molecular damage is so deeply in our ‘souls’ that one may wonder how TOR can cause aging other than via the accumulation of molecular damage. And what can cause molecular damage other than ROS? Then the argument becomes circular: if ROS does not cause aging, then TOR does not cause it either. Some potential mechanisms of how TOR limits lifespan were discussed previously and other mechanisms I will discuss in a forthcoming book on aging. In brief, there is no indication that TOR causes molecular damage. This is important to emphasize. And there is no reason to postulate a priori that aging is accumulation of molecular damage. TOR stimulates translation. This could explain why inhibition of translation increases lifespan.70,71 TOR inhibits autophagy (selfeating by lysosomes).31 And inhibition of autophagy is involved in aging. 72-75 TOR causes cell mass growth (cell hypertrophy), stimulates ribosomal synthesis, induces accumulation of aggregation-prone proteins, increases growth factors (GF) secretion and causes resistance to GF and insulin. In brief, TOR causes cellular hyperfunction. This hyperfunction secondarily causes cellular (not molecular) damage and organ failure. On the organismal level, these cellular hyperfunction, hypertrophy and hyperplasia are manifested as age-related diseases. These diseases culminate in cellular (not random molecular) damage, including cell death and organ failure.
Mammals do not die from healthy aging, they die from agerelated diseases. TOR is involved in all of them.2,67-69 In other words, TOR limits lifespan by accelerating age-related diseases. These diseases terminate lifespan in mammals, before the accumulation of molecular damage may reach clinical threshold. One may argue that diseases of aging have nothing to do with aging (except that they limit lifespan). Yes, they have little to do with aging, if aging is defined as an accumulation of molecular damage. But if aging is driven by TOR, then age-related diseases are deadly manifestations of TOR-driven aging. Of course these manifestations are different in humans and flies. Although neurodegeneration in flies also serves as a model for human diseases,31 mechanisms of TOR-driven aging in flies are too preliminary to be discussed here. But regardless of the mechanism, the fact is that genetic inhibition of the TOR pathway prolongs lifespan.By inhibiting autophagy,82,83 TOR may promote aging (Fig. 4).
The term autophagy means degradation of intracellular components in lysosomes. In simple words, TOR decreases lysosomal degradation of intracellular components. This is biologically logical. TOR is activated by nutrients, stimulates synthesis of intracellular components and inhibits autophagy. Aging is associated with a decline in lysosomal functions, leading to accumulation of lipofuscin, defective mitochondria and aggregationprone proteins.72,84-87 Furthermore, the anti-aging effect of calorie restriction (CR) was linked to autophagy.88-90 But why do lysosomes
become unable to degrade whatever was created? And how could lysosomal insufficiency be reconciled with other age-related alterations such menopause and insulin-resistance? The later changes couldbe explain
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