Biology subjects

Nespital, T.

Publications and source records attributed to Nespital, T..

3 recordsLinked to original sources

bioRxiv2024

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Genetic suppression of activity of the insulin/IGF/mTORC1/Ras network can ameliorate the effects of ageing in animals. The network provides multiple drug targets because of its role in metabolic disease and cancer, and these are candidates for repurposing for geroprotection. For instance, inhibition of the activity of the mTORC1 complex by rapamycin can extend lifespan in multiple organisms including mice, with early indications of efficacy in humans. Trametinib inhibits MEKs in the Ras pathway and can extend lifespan in Drosophila. However, it is not yet known if trametinib alone or in combination with rapamycin can extend mouse lifespan or improve health at older ages. We assessed survival and health indices of female and male mice treated with trametinib or rapamycin alone, or with the two in combination at the same doses. Trametinib treatment extended lifespan in both sexes, while its combination with rapamycin caused further, additive prolongation. Combination treatment reduced liver tumours in both sexes and spleen tumours in males, and ameliorated the age-related increase in brain glucose uptake. There was a striking reduction in inflammation in the brain, kidney, spleen and muscle with combination treatment, accompanied by reduced circulating levels of pro-inflammatory cytokines. Trametinib alone is therefore geroprotective in mice, but combined trametinib and rapamycin treatment is more geroprotective than treatment with either drug alone, suggesting immediate translational potential for humans.

physiology↗

bioRxiv2022

Reduced insulin signalling in neurons induces sex-specific health benefits

Reduced activity of the insulin/IGF signalling (IIS) network extends healthspan and lifespan in mammals and possibly humans. Loss of the Irs1 gene increases survival in mice and causes tissue-specific changes in gene expression. However, the tissues underlying IIS mediated longevity are currently unknown. Here we measured survival and healthspan in male and female animals lacking Irs1 activity specifically in the liver, muscle, fat and brain. Tissue-specific loss of IRS1 did not increase survival, suggesting that lack of Irs1 in more than one tissue is required for lifespan extension. Furthermore, loss of Irs1 in liver, muscle and fat did not improve health at old age. In contrast, loss of neuronal Irs1 increased energy expenditure, locomotion and insulin sensitivity, specifically in old males. Neuronal loss of IRS1 also caused male-specific mitochondrial dysfunction, activation of Atf4 and metabolic adaptations consistent with an activated integrated stress response at old age. Thus, we identified a male-specific brain signature of ageing in response to reduced IIS associated with improved health outcomes at old age.

neuroscience↗

bioRxiv2022

Full geroprotection from brief rapamycin treatment by persistently increased intestinal autophagy

The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side-effects from continuous dosing regimes. Here we show a profound memory effect of brief, early rapamycin treatment of adults, which extended lifespan in Drosophila to the same degree as lifelong dosing. Lasting memory of earlier rapamycin treatment was mediated by elevated autophagy in enterocytes of the gut, accompanied by increased levels of intestinal lysosomal alpha-mannosidase V (LManV), proteins involved in branched-chain amino acid metabolism and lysozyme levels, and by maintained structure and function of the ageing intestine. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a short-term, 3-month treatment in early adulthood also induced a memory effect, with maintenance similar to that seen with chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn. The geroprotective effects of chronic rapamycin treatment can thus be obtained with a brief pulse of the drug in early adulthood.

physiology↗