Kick the kebab, bin the burger, axe the avocado toast?! While caloric restriction represents a hunger-inducing yet effective means to extend lifespans, a tasty new study highlights how “hungry-hungry histones” create a neural hunger “state” that slows aging (even when getting our fill), suggesting that growing old may be more delicious than we think!
While “going hungry” can significantly slow aging, studies show that our diet’s effect on aging and behavior may share mechanistic foundations in promoted motivational states. The fruit fly Drosophila develops motivational drives for protein, with the mere perception of protein-containing food reversing the benefits of a protein-restricted diet through the activity of neurons whose loss significantly increases lifespan under nutrient-rich conditions. This inspired ravenous researchers led by Kristina Weaver and Scott Pletcher (University of Michigan, Ann Arbor) to evaluate whether neural states that encode the motivation for a “snack attack” slow aging. Their sweet and sour study now reports that “hungry-hungry histones” in neurons may help to induce a hunger state that slows aging.
Let’s hear from Weaver and colleagues, whose motivation directed them to the lab without stopping for coffee and cake:
- Limiting branched-chain amino acids (BCAAs) or activating hunger-promoting neurons via optogenetics induces a hunger state that extends the lifespan of female flies despite the consumption of more calories and total protein
- Specifically, dietary isoleucine modulates protein-specific appetite, which shows that a BCAA-limited diet promotes a heightened state of hunger by influencing protein drive
- BCAA limitation reduces histone H3 abundance and lowers histone H3K9 and H3K27 acetylation in neurons (possibly through the altered production of acetyl-CoA via BCAA metabolism) but increases H3.3 incorporation
- Activating hunger-promoting neurons also reduces histone H3 abundance in fly neurons, revealing that altering histone modification patterns correlates with one/both hunger phenotypes
- Adding isoleucine during BCAA limitation partially recapitulates the effects of BCAAs on histone H3 abundance
- Histone deacetylase inhibition increases feeding during BCAA limitation in the short term and extends the lifespan of BCAA-fed flies in the long term
- Therefore, modulating histone acetylation patterns influence both feeding and lifespan
- Inhibiting H3.3 usage abolishes increases feeding during BCAA limitation but does not affect lifespan, suggesting that differential histone H3/H3.3 usage modulates feeding but not lifespan in response to hunger
- Acute hunger increases feeding through histone variant H3.3 use, whereas prolonged hunger decreases a hunger “setpoint” to provide beneficial consequences for aging
While the burgers may remain on the table, staying hungry still seems crucial to slowing the aging process, given that the authors demonstrate that hunger – or the histone modification patterns in neurons that induce the hunger state – suffices to extend lifespan. Furthermore, this delectable dish of data also provides support for motivational states as deterministic drivers of aging.
“We’ve sort of divorced [the life extending effects of diet restriction] from all of the nutritional manipulations of the diet that researchers had worked on for many years to say they’re not required,” said co-lead author Scott Pletcher. “The perception of not enough food is sufficient.”
For more delicious details on how hungry-hungry histones help to slow the aging process, see Science, May 2023.