Study finds link between nonalcoholic fatty liver disease and stroke

August 07, 2017

"Curiously, ETC manipulation had to occur within a critical time window in a worm's lifespan to get the maximal effect," says Dillin, noting that effects were long-lasting. "It was like you could manipulate mitochondria in a 30-year-old human and get an extra 15 years, while in an 80-year-old, you might only gain two or three years."

To determine how cells respond to the pro-longevity cue, the group monitored a cellular emergency plan called the Unfolded Protein Response (UPR). Cells mount it when proteins accumulate excessively and begin to unravel-or "misfold"-which is toxic to cells. To avert cell death, the UPR mobilizes a team of helpers who, like sales clerks at a Gap sweater table, refold accumulating misfolded proteins piling up inside a cell.

When Dillin and colleagues fed worms reagents blocking the UPR, they found that disruption of cco-1 in neurons or intestine no longer had a lifespan-enhancing effect. This dramatic finding illustrates that initiating refolding of proteins, in this case in response to faraway mitochondrial stress, is in fact the very activity that enhances longevity.

Before 2000, biology textbooks defined mitochondria solely in terms of energy production. "We were caught up in mitochondrial metabolic function," says Dillin, remarking that pro-longevity signals characterized in the current study aren't strictly metabolic. "But we now recognize numerous other critical activities performed by mitochondria."

For example, a "metabolic" explanation for enhanced longevity, known as the "rate of living" theory, goes like this: revved up mitochondria burn cells' energy candle at both ends, leading to (your) premature demise. Conversely, cells that parsimoniously spend energy-possibly due to compromised mitochondrial output-live longer.

Dillin's study refutes this scenario. "We show that it all comes down to protein folding," says Dillin. "That's become the unifying theme in my lab."

Source: Salk Institute