The Secret of Aging and Longevity Lies in Connections Beyond the Genes

For some time, researchers have considered the theory that aging results from the accumulation of DNA changes, especially mutations. Accumulated mutations were thought to cause gene malfunctions that subsequently damage tissues and organs, triggering age-related disease processes. However, new research findings suggest that other factors, including epigenetic changes (changes beyond the genes that regulate how genes work), may actually be the main causes of aging.

The nuclei of our cells contain the complex DNA molecule, which provides long-term storage of genetic information and carries the genetic instructions necessary for the continuation of generations and biological development. The instructions in DNA are expressed through genes, and the complete set of instructions in DNA is called the genome . Epigenetic mechanisms enable genes to work in an orderly manner.

Epigenetics is the science of how genes can be influenced by nongenetic factors, including lifestyle and environmental factors such as sunlight exposure, smoking, the foods we eat, our physical activity, and the air we breathe. Epigenetic changes are not changes in the DNA sequence, but changes in how genes are expressed—that is, whether they are expressed as "active" or "inactive." Epigenetic factors control which genes are active or inactive in cells. The full set of elements involved in epigenetic regulation and mechanisms is called the epigenome .

Changes in molecular structures, and consequently in their functions, underlie biological aging. Changes in the energy states of biomolecules occur as a result of entropic changes. Entropy means the dispersal of concentrated energy, regardless of whether a system is open or closed. The ability to adapt to these changes in energy states can be maintained until maturity. After the productive or reproductive period, this balance in living organisms gradually deteriorates; molecules become more likely to become inactive because of changing energy states, and the body's immunity begins to weaken.

An Important Cause of Aging: Loss of Epigenetic Information

A study published in January 2023 in Cell showed that changes in the epigenome can accelerate or reverse aging.

In mice, the researchers mimicked certain changes caused by lifestyle or environmental factors in human and other mammalian cells. The changes causing epigenetic dysfunction were observed to biologically age the mice. In the second part of the study, the researchers administered gene therapy using genes active in stem cells. The gene therapy was found to reverse the aging-related epigenetic changes that the researchers had induced.

David Sinclair, a professor of genetics at the Blavatnik Institute at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research, and his team tested their hypothesis about the role of epigenetic changes in aging using a system called "ICE" (inducible changes to the epigenome). In this system, epigenetic changes in mice were induced by cutting their DNA to mimic changes caused by lifestyle or environmental factors in mammalian cells. Care was taken to ensure that repeated cuts in the DNA did not cause mutations in protein-coding regions.

An organism's chronological age is based on the days, months, and years it has lived, whereas biological age is measured using biomarkers of aging. Signs of biological aging in humans include dysfunction of mitochondria (the power sources of our cells) and shortening of telomeres (the capped ends of our chromosomes). Our biological age can differ greatly from our chronological age.

The researchers observed epigenetic chaos in ICE mice, supporting their hypothesis. Epigenetic factors were observed to stop their normal functions, move to chromosome breaks to perform repairs, and then return to their original locations. Over time, however, epigenetic malfunctions began to occur as some epigenetic factors stopped returning to their original locations. (The study did not specify which epigenetic factor took part in repair and failed to return to its original position.)

They observed that epigenetic malfunctions increased biomarkers of biological aging in ICE mice, causing them to look and behave older. The health of tissues and organs deteriorated and failed because cells lost their identities. (Every cell in our body has the same genes, but also has an identity as a skin cell, blood cell, bone cell, and so on.) Using a computational model to determine the biological age of ICE mice and compare it with that of non-ICE mice of the same chronological age, the researchers compared biologically unaltered mice with ICE mice and found that the ICE mice had aged more.

As an additional component of the experiment, the researchers gave ICE mice a gene called OSK, a combination of Oct4, Sox2, and Klf4, which are active in stem cells (gene therapy), to observe the treatment's effects on aging in ICE mice. Although the cells were seen to regain their lost epigenetic information when gene therapy was administered, the researchers are unsure what drives this process or how. One theory is that mammalian cells have a backup system resembling epigenetic information that, under appropriate conditions, could help reset or restore epigenetic function.

Sinclair's research on extending lifespan shows that manipulating the epigenome can both accelerate and reverse aging. Further knowledge in this area is thought to have the potential to help identify ways to prevent or reverse age-related processes and diseases such as Type 2 diabetes, cardiovascular disease, and cognitive impairment. These advances could improve quality of life in older years as well as extend lifespan. In light of this preliminary mouse study, further research is needed to determine how epigenetic manipulation could potentially be applied in humans.