Protein stability in naked mole rat could provide vital clues in the fight against aging, researchers hope.
"Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, say a group of US scientists in a paper published recently in the Proceedings of the National Academy of Sciences.
"When we compare the lab mouse with the naked mole rat, we find a striking difference in their systems," said study co-author Asish Chaudhuri, a University of Texas Health Science Center biochemist. "Their proteins are still working. Even when damaged, the functions are maintained."
Mitochondria are compartments within a cell that are dedicated to energy production, and their loss is thought to be a major cause of aging.When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is becoming more and more common.
Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.
Anti-aging drugs work by stimulating enzymes that regulate the function of mitochondria.
Chaudhuri's team's findings don't contradict the role of mitochondria, but expand the theory to include cellular proteins other than DNA. They also explain a condundrum: some long-lived species display plenty of oxidative damage.
"We've studied a dozen species, half short-lived and the others long-lived. One long-lived species would have lots of oxidative damage, and another would have little. The one thing that seemed to be consistent was protein stability," said University of Texas Health Sciences Center gerontologist Steven Austad, who was not involved in the current study. "Until recently I've focused on DNA damage and repair, but this strikes me as even more fundamental. For DNA repair to work, you need all the repair proteins to work properly."
Mole rats caught the researchers' attention because they can live for 30 years, or ten times longer than lab mice, even though the two are similarly sized.
They found that mole rats do have efficient mitochondria that release fewer free radicals than expected. But their mitochondria aren't perfect. Free radicals still gather and cause damage. Two-year-old mole rats show just as much oxidative stress two-year-old mice — and then live for another quarter-century.
The key appears to be their proteins, which continue to function despite damage. Study co-author Rochelle Buffenstein, a University of Texas Health Sciences Center physiologist, likened the phenomena to rusting cars: in other species, the axles rust, but in naked mole rats, it's just the doors.
With heat and urea — both of which typically cause complex protein spools to unfold — the researchers tried to break down the proteins, but to no avail.
"You can basically hit them with a sledgehammer, and the proteins don't unfold," said Buffenstein. "Something makes them inherently more stable. There might be small molecules that tack on to proteins and help them retain structure in the face of cellular stress."
Mole rats also appear to delay protein repair until the last possible moment, thus saving energy and resources. When proteins finally do break down, mole rats do an especially efficient job of cleaning them up. Only a tiny bit of ubiquitin — the chemical tag used to label damaged proteins for disposal — is required, Brandon Keim wrote on the Wired.
Finally, specialized protein-disposal structures, called proteosomes, don't appear to break down with age in mole rats.
The researchers will next try to determine what maintains the mole rat's proteins and proteosome. If, as Buffenstein suspects, it turns out to be an as-yet-unidentified protein protectant, scientists could apply the findings to people.
"If we can identify those proteins, we can use them to study aging and age-related diseases. These animals don't have any symptoms of neurodegeneration, even in old age," said Chaudhuri. "Then we can design peptides that act like the protein, and take it as a drug."