Researchers have discovered a cause of aging in mammals that may be reversible: a series of molecular events that enable communication within cells between the nucleus and mitochondria.

As communication breaks down, aging accelerates. By administering a molecule naturally produced in the human body, scientists were able to restore the communication network in older mice. Tissue samples taken afterward showed key biological markers similar to those of much younger animals.

"The aging process we discovered is like a married couple – when they are young, they communicate well, but over time, after many years of living closely, communication breaks down," said Professor of Genetics at Harvard Medical School, David Sinclair, the senior author of the study. "And like with a couple, restoring communication solved the problem."

This study was a joint project between Harvard Medical School, the National Institute on Aging (NIA), and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

Communication Breakdown

Mitochondria are often called the "powerhouse" of the cell, producing chemical energy to perform vital biological functions. These self-aware organelles, which live inside our cells and contain their own small genomes, have long been identified as key biological players in aging.

But as they become less efficient over time, many age-related diseases, such as Alzheimer's disease and diabetes, gradually develop.

Researchers have generally been skeptical about the idea that aging can be reversed, mainly due to the prevailing theory that age-related diseases result from mutations in mitochondrial DNA – and mutations are not reversible.

Sinclair and his group have studied the basic science of aging – broadly defined as a gradual decline in function over time – for many years, focusing primarily on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, is activated by the compound resveratrol found in grapes, red wine, and certain nuts.

Ana Gomes, a postdoctoral scientist in Sinclair's lab, studied mice in which this SIRT1 gene was removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins originating from the cell nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
"This was contrary to what the literature suggested," said Gomes.

Reversing Aging by Restoring NAD

As Gomes and her colleagues investigated possible reasons for this, they discovered a complex chain of events starting with a chemical called NAD and ending with a key molecule that transmits information and generates activities between the cell's nuclear genome and the mitochondrial genome. Cells remain healthy as long as the coordination between the genomes remains fluid. SIRT1's role is as a mediator, similar to a security guard; it ensures that a disruptive molecule called HIF-1 does not interfere with communication.

For reasons that are still unclear, as we age, levels of the initial chemical NAD decline. Without enough NAD, SIRT1 loses its ability to monitor HIF-1. HIF-1 levels rise and begin to damage the smooth communication between the genomes. Over time, the research team found, this loss of communication reduces the cell's ability to produce energy, and signs of aging and disease become apparent.

"This component of the aging process has never been described before," said Gomes.

While the collapse of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes discovered that by administering a precursor compound that cells convert into NAD, she could repair the broken network and quickly restore communication and mitochondrial function. If the compound was given early enough – before excessive accumulation of mutations – within days, some aspects of the aging process could be reversed.

Link Between HIF-1 and Aging and Cancer

Examining muscles from two-year-old mice that received the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation, and muscle wasting. In all three cases, the mice's tissue resembled that of six-month-old mice. In human years, this would be like a 60-year-old becoming 20 in these specific areas.

A particularly important aspect of this finding relates to HIF-1. More than a disruptive molecule that sabotages communication, HIF-1 is normally activated when the body is deprived of oxygen. Otherwise, it remains dormant. However, cancer is known to activate and hijack HIF-1. Researchers are still testing the exact role HIF-1 plays in cancer growth.

"It is very important to discover that a molecule activated in many types of cancer is also activated during aging," said Gomes. "We are beginning to see now that the physiology of cancer is similar in some ways to the physiology of aging. Perhaps this could explain why the greatest risk for cancer is age."

"There is clearly much more work to be done here, but if these results hold true, then certain aspects of aging may be reversible if caught early," said Sinclair.

The researchers are now testing the long-term results of the NAD-producing compound in mice and how it affects the entire mouse. They are also testing whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases like type 1 and type 2 diabetes. In the long term, Sinclair plans to test whether the compound will give mice healthier and longer lives.

Research Funding

Sinclair's lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the American Federation for Aging Research, the Ellison Medical Foundation, the SENS Research Foundation, and the Paul F. Glenn Center for Biology of Aging Research.

Potential Effects on Human Health

Sinclair and his colleagues' groundbreaking research may lead to the development of new drugs that could slow or even reverse the aging process. These drugs could help prevent or treat age-related diseases such as heart disease, diabetes, Alzheimer's, and cancer.

However, it is important to note that the research is still in its early stages, and further research is needed before these discoveries can be translated into effective treatments for humans.

References:
https://sinclair.hms.harvard.edu/