A New—and Reversible—Cause of Aging
A naturally produced compound rewinds aspects of age-related demise in mice
Mitochondria, organelles on the right, interact with the cell’s nucleus to ensure a healthy, functioning cell. Image by Ana Gomes Researchers have discovered a cause of aging in mammals that may be reversible.
The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable 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, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”
This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.
The findings are published Dec. 19 in Cell.
Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.
Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.
Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.
Sirt1 protein, red, circles the cell’s chromosomes, blue. Image by Ana GomesAna Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which thisSIRT1 gene had been 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 coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
“This was at odds with what the literature suggested,” said Gomes.
As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.
For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.
“This particular component of the aging process had never before been described,” said Gomes.
While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.
When Sirt1 loses its ability to monitor HIF-1, communication between mitochondria and the nucleus breaks down, and aging accelerates. Image by Ana Gomes
Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.
One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.
“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”
“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.
The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.
The Sinclair lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation and a gift from the Schulak family.
By DAVID CAMERON 19/12/2013
Turning back time: ageing reversed in mice
Imagine if we could turn back time. A team that has identified a new way in which cells age has also reversed the process in old mice whose bodies appear younger in several ways. The discovery has implications for understanding age-related diseases including cancers, neurodegenerative disorders and diabetes.
One way all mammalian cells produce energy is via aerobic respiration, in which large molecules are broken down into smaller ones, releasing energy in the process. This mainly occurs in the mitochondria – the “powerhouses” of cells. Mitochondria carry their own genomes, but some of the cellular components needed for respiration are produced partly by the nucleus, so the two must coordinate their activities.
As we age, mitochondrial function declines, which can lead to conditions such as Alzheimer’s disease and diabetes. To investigate why this decline occurs, Ana Gomes at Harvard Medical School and her colleagues compared the levels of messenger RNA (mRNA) – molecules that convey genetic information around a cell – for the cellular components needed for respiration in the skeletal muscle of 6 and 22-month-old mice.
They found that the level of the mRNA in the nucleus did not change much between the young and old mice, whereas those from the mitochondria appeared to decline with age.
Similar changes were seen in mice that lacked a protein called SIRT1 – high levels of which are associated with calorie restriction and an increased lifespan. These mice also had higher levels of a protein produced by the nucleus called hypoxia inducible factor (HIF-1α).
What was going on? It appears that communication between the nucleus and the mitochondria depends on a cascade of events involving HIF-1α and SIRT1. As long as SIRT1 levels remain high and the two genomes communicate well, ageing is kept at bay. But another molecule called NAD+ keeps SIRT1 on the job; crucially, the amount of NAD+ present in the cell declines with age, though no one knows why, leading to a breakdown in communication.
Turning back time
The team wondered if this aspect of ageing could be reversed by increasing the amount of SIRT1 in the cells. To find out if that was possible, they injected 22-month-old mice twice daily for a week with nicotinamide mono nucleotide (NMN) – a molecule known to increase levels of NAD.
At the end of the week, markers of muscular atrophy and inflammation had dropped and the mice had even developed a different muscle type more common in younger mice. Together, these features were characteristic of 6-month-old mice.
“We found that modulating this pathway can improve mitochondrial function and age-associated pathologies in old mice, and therefore it gives a new pathway to target that can reverse some aspects of ageing,” says Gomes.
“This paper clearly demonstrates that NAD+ production is a sort of ‘Achilles’ heel’, [a lack of which] significantly contributes to ageing, and also that this problem can be ameliorated by boosting NAD+ production with key intermediates, such as NMN,” says Shin-Ichiro Imai, at Washington University School of Medicine in St Louis, Missouri.
Journal reference: Cell, DOI: 10.1016/j.cell.2013.11.037
by Laasya Samhita