The lab of Whitehead Institute Member Siniša Hrvatin studies daily torpor, which lasts several hours, and its longer counterpart, hibernation, in order to understand their effects on tissue damage, disease progression, and aging. In their latest study, published in Nature Aging on March 7, first author Lorna Jayne, Hrvatin, and colleagues show that inducing a prolonged torpor-like state in mice slows down epigenetic changes that accompany aging.

Aging is a complex phenomenon that we’re just starting to unravel,says Hrvatin, who is also an assistant professor of biology at Massachusetts Institute of Technology. Although the full relationship between torpor and aging remains unclear, our findings point to decreased body temperature as the central driver of this anti-aging effect.

Tampering with the biological clock

Aging is a universal process, but scientists have long struggled to find a reliable metric for measuring it. Traditional clocks fall short because biological age doesn’t always align with chronology—cells and tissues in different organisms age at varying rates.

To solve this dilemma, scientists have turned to studying molecular processes that are common to aging across many species. This, in the past decade, has led to the development of epigenetic clocks, new computational tools that can estimate an organism’s age by analyzing the accumulation of epigenetic marks in cells over time.

Think of epigenetic marks as tiny chemical tags that cling either to the DNA itself or to the proteins, called histones, around which the DNA is wrapped. Histones act like spools, allowing long strands of DNA to coil around them, much like thread around a bobbin. When epigenetic tags are added to histones, they can compact the DNA, preventing genetic information from being read, or loosen it, making the information more accessible. When epigenetic tags attach directly to DNA, they can alter how the proteins that read a gene bind to the DNA.

While it’s unclear if epigenetic marks are a cause or consequence of aging, this much is evident: these marks change over an organism’s lifespan, altering how genes are turned on or off, without modifying the underlying DNA sequence. These changes have enabled researchers to track the biological age of individual cells and tissues using dedicated epigenetic clocks.  

In nature, states of stasis like hibernation and daily torpor help animals survive by conserving energy and avoiding predators. But now, emerging research in marmots and bats hints that hibernation may also slow down epigenetic aging, prompting researchers to explore whether there’s a deeper connection between prolonged bouts of torpor and longevity.

The age-old mystery
The researchers began by injecting adeno-associated virus in mice, a gene delivery vehicle that enables scientists to introduce new genetic material into target cells. They employed this technology to instruct neurons in the mice’s avMLPA region to produce a special receptor called Gq-DREADD, which does not respond to the brain’s natural signals but can be chemically activated by a drug. 

The mice were kept in a torpor-like state with periodic bouts of arousal for a total of nine months. The researchers measured the blood epigenetic age of these mice at the 3-, 6-, and 9-month marks using the mammalian blood epigenetic clock. By the 9-month mark, the torpor-like state had reduced blood epigenetic aging in these mice by approximately 37percentage, making them biologically three months younger than their control counterparts.

To isolate the effects of reduced metabolic rate, the researchers induced a torpor-like state in mice, while maintaining the animal’s normal body temperature. After three months, the blood epigenetic age of these mice was similar to that of the control group, suggesting that low metabolic rate alone does not slow down epigenetic aging.

Source: https://wi.mit.edu/news/manipulating-time-torpor