Overexpression of Atg5 in mice activates autophagy and extends lifespan

  title={Overexpression of Atg5 in mice activates autophagy and extends lifespan},
  author={Jong-Ok Pyo and Seung-Min Yoo and Hye-Hyun Ahn and Jihoon Nah and Se-hoon Hong and Tae-In Kam and Sunmin Jung and Yong-Keun Jung},
  journal={Nature Communications},
Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function… 

Autophagy and Longevity

Recent progress regarding the role of autophagy in lifespan regulation is summarized and pharmacological treatments have been shown to extend lifespan through activation of Autophagy, indicating autophagic activity could be a potential and promising target to modulate animal lifespan.

Autophagy as a promoter of longevity: insights from model organisms

Recent studies in model organisms uncovered prominent links between autophagy and ageing, suggesting that by removing superfluous or damaged cellular content through lysosomal degradation, Autophagy supports tissue and organismal fitness and promotes longevity.

Autophagy and Ageing

This chapter summarizes the current knowledge of the links between autophagy and ageing in C. elegans and suggests how long-lived animals may induceAutophagy to improve their overall healthspan, or how autophileagy is regulated in different tissues during normal ageing.

Suppression of autophagic activity by Rubicon is a signature of aging

Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several

Disruption of the beclin 1/Bcl-2 autophagy regulatory complex promotes longevity in mice

A knock-in mutation in beclin 1 that increases autophagy in mice extends animal lifespan, improves healthspan, and also rescues early lethality in mice deficient in the anti-ageing protein klotho.

Autophagy and Aging

Temporal inhibition of autophagy reveals segmental reversal of aging with increased cancer risk

It is demonstrated that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals and uncovers a biphasic role of Autophagy in cancer development being both tumor suppressive and oncogenic, sequentially.

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

It is demonstrated in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis, and uncovers a biphasic role in cancer development being both tumour suppressive and oncogenic, sequentially.

Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging

It is suggested that autophagic activity normally decreases with age in C. elegans, whereas daf-2 and glp-1 long-lived mutants regulate autophagy in distinct spatiotemporal-specific manners to extend lifespan.

Autophagy slows the aging of Germline stem cells in Drosophila through modulation of E-cadherin

The data suggests that elevated autophagy promotes GSC maintenance and activity, and delays their aging, and suggests that Atg8aOE GSCs occupy the stem cell niche for longer duration with the aid of elevated E-cadherin at the GSC-cap cell contact sites.



Autophagy Regulates Ageing in C. elegans

It is shown that RNAi shortened the lifespan of both wild type and daf-2 mutant C. elegans, providing strong support for a role of autophagy in ageing regulation.

Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice

Conditional knockout mice of Atg7 were generated and showed the important role of autophagy in starvation response and the quality control of proteins and organelles in quiescent cells.

Induction of autophagy by spermidine promotes longevity

Administration of spermidine markedly extended the lifespan of yeast, flies and worms, and human immune cells and inhibited oxidative stress in ageing mice, and found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

Autophagy genes and ageing

  • T. Vellai
  • Biology
    Cell Death and Differentiation
  • 2009
Genetic studies show that autophagy-related genes are required for lifespan extension in various long-lived mutant nematodes and promote survival in worms and flies exposed to prolonged starvation, and results in Drosophila demonstrate that promoting basal expression of the Autophagy gene Atg8 in the nervous system extends lifespan by 50%, thereby providing evidence that the autophile pathway regulates the rate at which the tissues age.

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

Autophagy-deficient mice develop multiple liver tumors.

The results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression.

Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans

It is demonstrated that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans and may act as a central regulatory mechanism of animal aging.

Autophagy in mammalian development and differentiation

The analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation.

Regulation of autophagy by cytoplasmic p53

Evidence is provided of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53, which improved the survival of p 53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels.