In a groundbreaking study more than 13 years in the making, researchers led by Harvard University’s Dr. David Sinclair may have just turned everything we thought we knew about aging on its head. For decades, the leading theory that explains why all living things age and eventually wither away and die is that aging is due to mutations in DNA as cells divide and proliferate over time. But Harvard scientists have now shown that DNA mutations are only part of the picture and a much grander role may be played by epigenetics. They proved their point by aging or reverse-aging mice at will with almost as much ease as flipping a switch.
The Information Theory of Aging
DNA is like a blueprint of life that contains the instructions needed for an organism to grow, develop, survive and reproduce. DNA does this by controlling protein synthesis. Each gene has a unique sequence that makes a distinct protein, and all the genes inside your body comprise the genome. When a gene mutates, it’s like a hardcopy change in one or more parts of the gene’s sequence.
Epigenetic changes, on the other hand, are genetic modifications that impact gene activity without changing the DNA sequence. One example of an epigenetic change is DNA methylation — the addition of a methyl group, or a “chemical cap,” to part of the DNA molecule, which prevents certain genes from being expressed. These epigenetic changes can be brought about by diet, stressors and environmental pollutants.
Imagine an orchestra playing at a grand concert. Each instrument in the orchestra is like a gene in your body, and the music they play is like the traits that gene controls. The conductor, or epigenetics, tells each instrument when to play and when to be quiet. This changes how the music sounds, just like how epigenetics changes how your genes work.
Epigenetics has gained a lot of interest over the years due to its immense potential in transforming healthcare. You see, when the body suffers genetic mutations, there’s really not much you can do. But if a health condition like cancer or Alzheimer’s is actually caused by an epigenetic change, then that situation is completely reversible. And Dr. Sinclair thinks the same is true for aging as well.
Professor Sinclair has put forth what he calls the “Information Theory of Aging’, which posits that aging in virtually all eukaryotes (that means us too) is due to the loss of epigenetic information over time, and not just the accumulation of mutations in cells. One way to view this is that cells age and start malfunctioning because of software glitches rather than damage to the underlying hardware. The fundamental implication of this major paradigm shift in how scientists view biological aging is that aging is much more reversible than thought, as long as you ‘patch’ the code.
All living cells in an organism contain the same exact genetic instructions, encoded into their DNA. The reason a cell may develop into a particularly specialized cell, such as a skin cell or neuron, has to do with epigenetic factors, which switch certain genes on and off leading to cellular differentiation.
Winding back the biological clock
During experiments, Sinclair’s group introduced breaks in the DNA of very young mice in order to accelerate aging like hitting the fast-forward button on Netflix. These breaks in the chromosomes were placed outside of the coding regions of the mice’s DNA, meaning no damage was done to the genes themselves, just to the areas between them. This prevents the mice from developing gene mutations and any changes would be solely due to the way DNA is folded.
Within weeks, the mice looked abnormally old for their chronological age, showing gray fur, lower body weight, less activity, and signs of frailty. The researchers pinned these effects to the fact that epigenetic factors, which should normally regulate genes, were disorganized and inactive, probably because they lost their original information.
But then the scientists used a viral gene therapy consisting of three genes — Oct4, Sox2, and Klf4 — part of the so-called Yamanaka stem cells factors, which are typically used to turn adult specialized cells, such as skin cells, into stem cells (technically called induced pluripotent stem cells). But this time, these factors didn’t reverse adult cells into stem cells but rather simply reset the cells’ epigenetic history and their underlying gene expression-altering instructions.
This therapy, known as “ICE” (Inducible Changes to the Epigenome) remarkably reversed the epigenetic changes, repairing DNA breaks and subsequently rejuvenating the mice, reversing the aging effects. The researchers concluded that, “with an ability to drive aging in both forward and reverse directions, the loss of epigenetic information is a cause of aging in mammals.”
The same technique was used by a different group from the biotech company Rejuvenate Bio to extend the lifespan of mice by as much as 109%. Previously, in 2020, Sinclair’s team used ICE to restore vision in older mice but the new findings show that rejuvenation can be achieved across the entire body and not just in a particular tissue or organ. It follows that, in theory at least, the same therapy could be used to reverse age-related illnesses that currently plague mankind, including currently incurable diseases like Alzheimer’s. In another study, Sinclair’s group also showed that using Yamanaka factors can reverse the epigenetic age of old neurons.
All of this sounds amazing, but will it work on humans? It’s not clear at all at this point because aging is such a complex process. Moreover, the new study, as exciting as its results may be, seems to raise more questions than it answers as it is still a mystery how exactly these epigenetic factors do all their rejuvenation work. The researchers just know that it works — somehow.
Sinclair and colleagues are now testing ICE in non-human primates. We’ll be following these developments closely as they may open the door to a new age of rejuvenation and longevity therapy that could touch the lives of billions of people.
The new findings appeared in the journal Cell.
