#1

I’m interested in people’s thoughts on a recent study in mice that showed those with shorter telomeres saw accelerated aging with rapamycin.

This may not translate to humans and it was just one study so I’m not reading too much into it. I’m currently on rapamycin 5mg a week. Genetics tests showed shorter telomeres but I’ve never had any symptoms associated with that. I’m just genuinely curious what affects there could be in this area, both positive and negative.

Except from study:
An mTOR inhibitor is rapamycin, a drug that prolongs life in yeasts, flies, worms and mice, and that significantly reduces the incidence of cancer in mice with normal telomeres.

The researchers wanted to test whether rapamycin could also extend the life of mice with short telomeres, but they found that the opposite happens: they age up to 50% faster. This basic finding allowed the authors to discover that mTOR is, in fact, important for the survival of mice with short telomeres, and therefore blocking it has a negative effect.

Link to study

Nature Communications. The CNIO finds that rapamycin has harmful effects when telomeres are short

  • Maria Blasco’s group at the CNIO shows that an anti-ageing strategy that extends life in normal mice, the treatment with rapamycin, is harmful when mice have short telomeres

  • The group addresses for the first time the connections between two of the main biochemical processes associated with ageing: the shortening of telomeres and the ability of cells to detect nutrients

  • The study, published in ‘Nature Communications’, reveals thus far unknown basic aspects of one of the main molecular pathways, mTOR, involved in cancer and ageing

  • The finding helps to better understand diseases such as aplastic anaemia and pulmonary fibrosis

In the past few decades, it was discovered that the rate at which we age is strongly influenced by biochemical processes that, at least in animal models, can be controlled in the laboratory. Telomere shortening is one of these processes; another one is the ability of cells to detect nutrients mediated by the mTOR protein. Researchers have been able to prolong life in many species by modifying either one of them. But what if we manipulate both? A team from the Spanish National Cancer Research Centre (CNIO) now studied it for the first time, with unexpected results. Blocking nutrient sensing by treatment with rapamycin, an mTOR inhibitor, delays the ageing of healthy mice but, curiously, it worsens diseases and premature ageing that occur in mice with short telomeres. This finding has important implications for the treatment of diseases associated with short telomeres, but also for age-related diseases that are also associated with short telomeres. The study, done by the Telomeres and Telomerase Group headed by Maria Blasco at the CNIO, is published in Nature Communications with Iole Ferrara-Romeo as the first author.

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#2

Telomeres in the house mouse, Mus musculus , are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer.

I suppose mice with telomere syndrome are not really that relevant to healthy humans.

Second, accumulation of molecular damage can be greatly accelerated artificially by knockout of repair/maintenance enzymes (Figure 1B). Such animals do not exist in nature. But artificially created, they may provide a glimpse of how post-aging may look. Their pathology differs drastically from normal aging, for example, telomere shortening. Second-generation telomerase-deficient mice (G2 Terc−/−) with critically short telomeres fail to grow and die young from unfamiliar diseases such as intestinal atrophy due to failure of cell proliferation [3]. When telomeres reach critical length, it can cause DNA-damage response, leading to aplastic anemia, organ fibrosis, atrophy of the small intestine and the spleen, skin and hair lesions. In humans, diseases of short telomeres cause death from bone marrow failure and pulmonary fibrosis [72]. This does not resemble normal aging.

In humans, mice and C. elegans, telomere shortening is not life-limiting [73–75]. In mice lacking telomerase, even accelerated telomere shortening is still not life-limiting in the first generation [76]. It took several generations to achieve critically short telomeres, leading to syndromes strikingly different from normal aging. In humans, telomere length does not reach telomere threshold during life time [75, 77, 78]. Normal telomere shortening would cause telomere-driven pathologies, but normal animals do not live long enough to reach this threshold. Rapamycin prolongs life in normal mice, proving that telomere length does not constrain normal lifespan [3]. When artificially shortened, then telomeres become life-limiting and rapamycin cannot extend lifespan anymore [3].

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