hyperfunction, TOR and anti molecular damage theory Flashcards
who came up with the hyper functionality hypothesis ?
Blagosklonny
what kind of damage does the wear and tear theory generally revolve around ?
ROS and oxidative damage
what has been the problem with the ROS theory and the wear and tear theory?
it can’t be disproved, data that doesn’t fit is simply incorporated
what is an example of ROS being shoe horned into ageing even when the data doesn’t fit?
- some studies found that increased ROS increased life span and this was turned into the hormesis theory
- antioxidant clinical studies have not been fruitful yet some argue this is because they are not using the right antioxidants even though these are the same ones used in model organisms
what 4 antioxidanst have been tested clinically to test their affects on ageing and what was the outcome
beta carotine, Vitamin E and C, retinol. None have shown any statistical decrease in age-related diseases and or mortality some were even stopped early due to increased incidence of disease
why is the argument that ROS levels increase uncontrollable not necessarily true and that instead they re regulated? what are the signalling pathways that prove this?
- cells express SOD and catalase: if they wanted to get rid of ROS they would simply increase the expression of these proteins and this process of recycling is not costly, there is no reason why it would be selected against
- there are positive feedback mechanisms that show this: increased ROS activate NRF2, wjocj stimulated antioxidantn and detoxification genes. H2O2 also stimulates NRF2
- ROS are not just unwanted by products of respiration, they are involved in functions such as inflammation and signalling pathways- they are also used by neutrophils by producing high levels of superoxide
- ROS qualify as authentic secondary messngers: there is nothing inherently deadly about ROS
why is the link between ROS and cell death not a good one?
it is argued that ROS kills BUT apoptosis and cell cycle arrest by ROS are regulated events- they activate p53 which then triggers it and even so it does this at very high, unphysiological levels
- but in the wear and tear idea- ROS causes damage by molecular damage
- at lower levels hydrogen peroxide actually can stimulate cell growth via the PI3K/TOR pathway
what is the evidence that DNA damage (from ROS presumably) limits life span?(1) or that it doesnt? (4)
- accumulation of DNA mutations correlated with ageing but is not necessarily causal.
- mice can be cloned from using the nuclei of an ageing animal- indicating there is no significant damage during lifespan
- in mice increased levels of ROS leads to increased levels of DNA damage but does not affect ageing.
- mutated mitochondiral genes
are the driving force behind the premature aging phenotype of mitochondrial mutator mice.Interestingly, the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis. However these mutatormice have hundreds-fold increase in mutation rate. It was calculated that in normal mice accumulation of mutations in mtDNA cannot be sufficient to cause aging.
-certainly, accumulation of molecular damage must sooner or later cause deterioration. - However, an organism may not live long enough to reach the “lethal threshold” of molecular damage.
what are two exceptions to the theory that accumulated mutations only cause damage at very high levels and how can this fit into the hyper function theory?
- mutations in oncogenes, cancer is a disease of ageing- but these cancer cells are extremely robust- not crippled and non-functioning Cancer cells have high levels of molecular damage but they are robust. This suggests that molecular damage in cancer cells is far below a deleterious threshold for such cells themselves.
- As a second example, mitochondria may undergo clonal propaga- tion, so that mutant mtDNA, if it provides a selective advantage, replaces wild-type mtDNA. Such accumulation of defective or ‘malig- nant’ mitochondria may occur with age due to inhibited autophagy (degradation in lysosomes) of mitochondria (reviewed in ref. 30). Accumulation of defective mitochondria probably plays a role in some diseases of aging such as hearing loss. And it is important that the TOR pathway inhibits autophagy. And rapamycin, an inhibitor of TOR, restores autophagy.31,32 If so, defective (“malignant”) mito- chondria are a pro-apoptotic effector of the TOR pathway. (hyper function)
what is the evidence against the ROS theory? (5)
- lifespan can be extended without ROS
- in the honeybee, the queen does not live longer because of increased ROS resistance
- antioxidants do not explain the disparities between mice and the longest living rodent
- oxidative damage levels are very high in the naked mole rat
- In mice, life-long reduction of SOD activity leads to increased levels of oxidative damage to DNA but does not affect aging
- Overexpression of Cu-Zn superoxide dismutase in Drosophila did not affect lifespan
what are the two strongest pieces of evidence of the ROS Theory and how does this fit into the TOR theory?
here are two additional models that are believed to support the ROS theory. In mice, a knockout of the p66Shc decreases ROS production and prolongs life span.herefore, an alternative explanation is that increased longevity of p66Shc knockout mice is due to inhibi- tion of the TOR pathway.
In Drosophila, the neurofibro- matosis-1 (NF1) gene mutants had shortened life spans, thus also supporting the ROS model (Fig. 2). Yet, as we will discuss, both NF1 and Shc are upstream regulators of the TOR pathway. NF1 is a well-known tumor suppressor whose loss results in constant activation of the TOR pathway. The TOR model of aging predicts that loss of NF1 will shorten lifespan due to TOR hyperstimulation. And this predic- tion has been actually confirmed by Tong et al., albeit without such a conclusion.81
how do the results of DR contradict the disposable soma theory?
t 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, starva- tion, 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 limitedallocate resources for anti-aging repair in order to live longer. But the generla theory of ageing is that it is not exposed to selection and does not limit lifespan in the wild but according to this theory it does because the animal has to actively defer it.This implies that aging limits both life span and reproduction in the wild. This cannot be reconciled with the evolutionary theory of aging.
how does the ROS theory imply that ageing is programmed and how is this wrong? how doe the TOR theory rectify this issue?
Aging cannot be programmed because it has no selective advan- tage. And, at first glance, ROS-induced aging is not programmed. Indeed damage itself is stochastic, random. But its repair is not random. According to the allocation model,52 an organism decides to repair or not to repair. It chooses to repair at a lesser extent when resources are plenty.52 If so, then aging is not only programmed but even regulated via allocation of resources. In contrast, according to the TOR-centric model, the link between nutrients and aging is mechanistic, not purposeful. Simply nutrients activate the nutrient- sensing TOR pathway.In contrast, according to the TOR-centric model, the link between nutrients and aging is mechanistic, not purposeful. Simply nutrients activate the nutrient- sensing TOR pathway.
why does the hormesis argument of ROS not make sense? how does the TOR theory rectify this?
Hormesis is extension of life span by mild and repeated stresses. Chronic cellular stress including ROS production may prolong life span.10 And reduction of ROS by antioxidants can shorten life span.10,53 It has even been suggested that the beneficial effects of physical exercise are partly based on the ROS generating capability of exercise.10 If induction of ROS prolongs life span (by whatever mechanism), then ROS simply cannot be a cause of aging. It seems paradoxical that ROS-induced repair prevents aging caused by ROSIn contrast, the TOR-centric model solves paradoxes. Some stresses (calorie restriction) inhibit TOR, thus slowing aging, whereas other stresses increase aging-tolerance without affecting aging itsel
what is the TOR pathway activated by? (3)
insulin, growth factors and nutrients
what does the activation of the TOR pathway result in? (8)
protein synthesis, stimulates cell mass growth, inhibits autophagy. stimulates GH secretion, stimulates ribosomal DNA synthesis, causes insulin resistance, stimulates ROS
when the cell cycle is blocked but TOR is still active, what happens? what does this resemble?
a cell becomes hypertrophic and hyperactive and secretes cytokines and mitogens and develops compensatory resistants to signals such as insulin and growth factors. in other words, it becomes senescent
what evidence is there for TOR being directly involved in longevity?
inhibition prolongs lifspan in yeasts, worms and flies- not yet known in mice??
in what animals has TOR inhibition been shown to increase lifespan
yeast, flies, c.elegans
what is the IGFR TOR pathway?
IGF-2, PI3K, AKT, TORm S6K
what genes for longevity inhibit TOR signalling? (5)
AMPK, PTEN, NF1( VIA ROS), SIR2, METFORMIN
what is metformin?
an anti-diabetic drug which extends lifespan in rodents and inhibits TOR
how does DR fit into the TOR pathway?
nutrients triggers the TOR pathway- less food= less tor= less hyper function= longevity
how is TOR thought to cause ageing? (6+general)
- TOR stimulates translation and inhibition of translation increases lifespan
- tor inhibits autophagy and inhibition of autophagy is involved in ageing and the effects of IIS mutants are partially dependent on autophagy
- TOR causes cell mass growth (cell hypertrophy)
- induces accumulation of aggregation prone proteins
- increasesgrwoth factor secretion
- causes resistant to GF and insulin
- in General TOR causes hyper function and this cellular (not molecular damage) causes organ failure and ageing
describe how cellular hyper function is manifested in disease of ageing?
- death of cardiomycotes during cardinal infarction- caused by insufficient blood supply due to arthersclerosis, increased coagulation and platelet hyper functionnflammation, high blood pressure and cardiomyocyte hypertrophy.
- As a second example, over-active osteoclasts (TOR-dependent) cause osteopo- rosis.76 Osteoporosis in turn leads to broken bones in the elderly. As a third example, FSH hyperproduction with age causes folliculardepletion in the ovaries, known as menopause
- Similarly, as a fourth example, overactivation of TOR in fat and skeletal muscle causes insulin resistance.Insulin resistance causes compensatory activation of beta-cells in the pancreas. This hyperactivation ulti- mately results in the failure of beta-cells and type II diabetes.
- And the most dramatic example is cancer, which causes failure of the organ, where tumors grow. Obviously, there is no “weakening” of cancer cells. In contrast, the problem is that they are too robust.
what is the problem with the autophagy idea of ROS/ W&T and how can the TOR reconcile this?
- autophagy is due to lysosomal insufficiency, and is associated with ageing due to the accumulation of lipofuscins. How can lysosomal insufficienty be reconciled with age-related alterations such a menopause and insulin resistance?
- the neuroendocrine theory: hyperstimulation and progressive signal-resistance of the hypothalamus and end-organs. For example, activation of nutrient-sensing pathways can cause insulin-resistance, which plays a key role in type II diabetes, obesity and hypertension. On the other hand, hypothalamic estrogen-resis- tance causes hyperstimulation of the ovaries, leading to menopauseWhat would then lysosomal insufficiency have in common with all these neuroendocrine alterations? I suggest that insufficient autophagy and neuroendocrine hormone resistance are tips of the iceberg: hyperactivation of the TOR pathway
what does the TOR theory make conciliable?
Thus, the TOR-centric model allows us to integrate lysosomal/autophagic and neuroendocrine theories, which otherwise seem irreconcilable.Both inhibition of autophagy and signal-resistance are a consequence of hyper-active TOR
what actually proves that autophagy slows ageing?
is that increased autophagy increases lifespan.93 So it is sufficient to increase autophagy by enhanced Atg8a expression in older fly brains in order to extend the average adult lifespan by 56%. The expression of a rate-limiting autophagy gene in neurons promotes longevity in Drosophila.
