The integrated stress response in cells acts to reduce protein synthesis while enhancing maintenance activities. A number of sensors for different forms of cell stress all converge on activation of the integrated stress response. These stresses include lack of nutrients, the presence of viral material, and too many unfolded proteins cluttering up the endoplasmic reticulum, among others. The degree of activation of the integrated stress response is important: mild activation is generally beneficial, but too much activation will produce apoptosis, the cell destroying itself in programmed cell death.
Like other stress response systems in the cell, some studies show that manipulation of the integrated stress response can modestly slow aging and extend life in short-lived species. Thus there is considerable research interest in the manipulation of the integrated stress response as a basis for therapy. A number of drugs capable of promoting or suppressing the integrated stress response exist already, and others are in development. The challenge in targeting the integrated stress response lies in the threading the needle of settling on enough activation to be useful, but not too little activation or too much activation, either of which can be harmful. What constitutes the right level of integrated stress response activation may vary between cell types in a tissue, between different tissues, and between individuals. Thus integrated stress response targeting drugs tend to have unpleasant side effect profiles.
Today's open access research paper illustrates this challenge in the move between laboratory species. The authors report that flies react quite differently to manipulation of the integrated stress response than nematode worms. Given the present state of medical technology, I do not think that we should be confident in the emergence of a very safe therapeutic approach to the adjustment of integrated stress response activity intended to slow aging. That is not to say it is impossible, it is just more difficult than would be cost-effective to attempt in the environment of what is readily possible today.
Recent progress in geroscience suggests that targeting broad aspects that underlie the biology of aging could prevent many age-related diseases simultaneously. One such treatment is the activation of stress response pathways. Recently, activation of the integrated stress response (ISR) orchestrated by the transcription factor ATF4 has been studied. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNA interference) of dATF4 extends lifespan.
We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity.
View the full article at FightAging
