The work conducted at Calico Labs is representative of the broad faction of the aging research community that aims to alter metabolism in order to modestly slow the progression of aging. The damaged and dysfunctional environment of aged tissues and cell structures produces cell stress via many different mechanisms. Cells respond to that stress in a smaller set of ways, and some of those responses are maladaptive, making the situation worse. The best way forward would be to repair the damage that causes cell stress; the approach taken here is to instead alter the behavior of cells in order to selectively sabotage some of the maladaptive response to cell stress.
The Integrated Stress Response (ISR) is a conserved signaling pathway across species and an important area of focus for Calico because of its possible link to many age-related diseases and its potential as a target for new drug development. Calico is currently developing an ISR inhibitor, Fosigotifator (ABBV-CLS-7262), which is being tested in the clinic as a potential treatment for two neurodegenerative diseases. To gain a deeper understanding of how the ISR controls cell states, the Calico team used a highly specific and tunable cellular model to disentangle the effects of the ISR from other processes that are engaged when cells encounter stress or damage that disrupts them.
A key discovery was the suppression of a process known as the tricarboxylic acid (TCA) cycle which is a series of reactions that are essential for creating energy via cellular respiration. The researchers found that when the ISR is turned on even at low levels, carbon is redirected from mitochondria to make amino acids and glutathione, a key antioxidant that protects cells. This shows how the ISR may help cells adapt to mitochondrial dysfunction or starvation, two common triggers of the pathway, by rewiring their metabolism. Using a synthetic tool researchers also showed that activation of the ISR can lead to the formation of droplets that store fats, also known as lipids. This is interesting because lipid droplets have been linked to neurodegenerative diseases.
Link: https://www.calicolabs.com/story/calico-scientists-get-a-close-up-look-at-cell-stress/
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