Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing

The field of the biology of ageing has received increasing attention from a biomedical point of view over the past decades. The main reason has been the realisation that increases in human population life expectancy are accompanied by late onset diseases. Indeed, ageing is the most important risk factor for a number of neoplastic, neurodegenerative and metabolic pathologies. Advances in the knowledge of the genetics of ageing, mainly through research in model organisms, have implicated various cellular processes and the respective signalling pathways that regulate them in cellular and organismal ageing. Associated with ageing is a dysregulation of metabolic homeostasis usually manifested as age-related obesity, diminished insulin sensitivity and impaired glucose and lipid homeostasis. Metabolic deterioration contributes to the ageing phenotype and metabolic pathologies are thought to be one of the main factors limiting the potential for lifespan extension. Great efforts have been directed towards identifying pharmacological interventions with the potential to improve healthspan and a number of natural and synthetic compounds have shown promise in achieving beneficial metabolic effects

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and healthspan in various model organisms. Amongst a number of body organs that sense and respond to insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan efects of IIS at the organismal level. Genetic inactivation of IIS components specifcally in the adipose tissue has been shown before to improve metabolic profle and extend lifespan in various model organisms. We sought to identify conserved molecular mechanisms that may underlie the benefcial efects of IIS inhibition in the adipose tissue, specifcally at the level of phosphoinositide 3-kinase (PI3K), a key IIS efector molecule. To this end, we inactivated PI3K by genetic means in the fy fat body and by pharmacological inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and upregulation of mitochondrial activity in mouse adipocytes and fy fat bodies with downregulated PI3K, which were confrmed by biochemical assays in mammalian adipocytes. These data suggest that PI3K inactivation has a conserved efect of upregulating mitochondrial metabolism in both fy and mammalian adipose tissue, which likely contributes to the health- and life-span extending efect of IIS pathway downregulation