After 13 years of research, Dr. David Sinclair and his team have finally discovered the key factors that drive aging, according to TIME.
A study published on January 12th in the journal Cell describes a revolutionary aging clock developed by Sinclair, a genetics professor and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, that can accelerate or reverse the aging process at the cellular level.
Scientists researching aging have long debated the underlying causes of senescence in cells. Historically, much attention has been given to mutations in DNA as the primary driver of this process, as these mutations can, over time, disrupt the normal functioning of cells and ultimately lead to cell death. However, this theory has been called into question by the observation that older individuals’ cells often do not contain a significant number of mutations and that individuals or animals with a higher burden of mutated cells do not appear to age prematurely.
Sinclair shifted his attention to the epigenome, a crucial aspect of the genome that dictates the development and function of different cells. While all cells possess the same DNA blueprint, it is the epigenome that tells certain cells to become skin cells and others to become brain cells. This is achieved by providing specific instructions to different cells, determining which genes are activated and which are suppressed. The concept of epigenetics can be compared to the instructions given to a dressmaker, where the starting fabric is the same, but the pattern dictates the final shape and function of the clothing. Similarly, in cells, the epigenetic instructions lead to differentiation, resulting in cells with distinct physical structures and functions.
In the Cell paper, Sinclair and his team reveal that they have not only successfully accelerated the aging process in mice but also reversed it, restoring biological signs of youthfulness to the animals. This ability to reverse the effects of aging supports Sinclair’s theory that the primary cause of aging is not mutations to DNA but rather errors in epigenetic instructions. Sinclair has long proposed that aging is caused by the loss of crucial instructions needed for cells to function, which he refers to as the Information Theory of Aging. According to Sinclair, “Aging is not just about the accumulation of damage, but also about the loss of information in cells – this is a paradigm shift in how we think about aging.”
Sinclair’s recent findings appear to corroborate his theory, comparing the process to the way software programs operate on hardware. He explains that sometimes these programs may become corrupt and require a reboot. “If aging were caused by a cell becoming overloaded with mutations, then reversing aging would not be feasible,” he states. “However, by demonstrating that we can reverse the aging process, it indicates that the system is still functional and that a reboot of the software is necessary.”
He and his team developed a method to reset cells in mice by restarting the backup copy of epigenetic instructions, effectively eliminating the faulty signals that cause cells to age. To replicate the effects of aging on the epigenome, they introduced DNA breaks in young mice. These types of epigenetic changes can also occur naturally due to factors such as smoking, exposure to pollution, and chemicals. After being “aged” in this manner, the mice began to exhibit signs of aging, such as graying fur, weight loss, decreased activity, and increased fragility, within a matter of weeks.
The process of rejuvenation was achieved through gene therapy that utilized three specific genes. These genes provided instructions for cells to reprogram themselves, allowing for the reversal of aging effects on cells such as those found in the kidneys and skin. These genes were taken from the Yamanaka stem cell factors, a set of four genes discovered by Nobel laureate Shinya Yamanaka in 2006 that can return adult cells to an embryonic stem cell state, allowing for the restart of their development. The goal was not to completely erase the cells’ epigenetic history but rather to reset it through a partial reboot of approximately 57% using three of the four factors. This was enough to restore youthfulness in the mice.
This study marks the beginning of a new understanding of aging, and Sinclair acknowledges that it opens up more questions than it provides answers for. He states, “While we may not fully comprehend the mechanisms of rejuvenation, we know that it is effective. We can utilize it to revitalize various aspects of the body and potentially create groundbreaking medicines. Now, when I encounter an older individual, I no longer view them as old but rather as someone whose system needs to be reinitialized. The question is no longer if rejuvenation is possible, but rather when it will become a reality.”