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Using Genetics to Reverse the Aging Process in Humans

By: Sai Srihaas Potu

Aging is characterized by progressive functional decline at the molecular, cellular, tissue, and organismal levels. As an organism ages, it becomes frail, its susceptibility to disease increases, and its probability of dying rises. In humans, age is the primary risk factor for various number of diseases including neurodegeneration and cardiovascular disease.


During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. One of the major goals of genetics research is to define biomarkers of aging, which can be thought of as individual-level measures of aging that capture inter-individual differences in the timing of disease onset, functional decline, and death over the life course.


In a new study, researchers have discovered the cause of aging in mammals. 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.


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 over time, 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 to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.


A group of researchers led by Ana Gomes 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.


Ana Gomes, a postdoctoral scientist, had been studying mice in which this SIRT1 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.


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.


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 were given early enough—before excessive mutation accumulation—within days, some aspects of the aging process could be reversed.


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.


One particularly important aspect of this finding involves HIF-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.


The results of this study show that a molecule that switches on in many cancers also switches on during aging. The researchers were able to conclude that the physiology of cancer has to be similar to the physiology of aging in certain ways. This can explain why the greatest risk of cancer is age.


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. Over the long run, Gomes plans to test if the compound will give mice a healthier, longer life.


Understanding the interaction of processes of aging and chronic diseases should be a high priority. Better alignment of preclinical studies on aging and human investigations is needed. Although significant progress has been achieved in characterizing aging-induced changes in human function, research efforts should persist in this direction to develop innovative strategies based on recent achievements in the biology of aging to improve a person’s health-span.


References:

1. Ana P. Gomes, Nathan L. Price, Alvin J.Y. Ling, Javid J. Moslehi, Magdalene K. Montgomery. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 2013.

2. Bocklandt S, Lin W, Sehl ME, Sánchez FJ, Sinsheimer JS, Horvath S, Vilain E. Epigenetic predictor of age. PLOS One. 2011.

3. Sebastiani P, Thyagarajan B, Sun F, Schupf N, Newman AB, Montano M, Perls TT. Biomarker signatures of aging. Aging Cell. 2017.

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