Professor Sinclair’s New Theory of Aging and Anti-Aging Mechanisms
- Seoyeon Lee
- Mar 18, 2024
- 5 min read
Introduction
Can humans live forever? Since ancient times dating back to four millennia in Mesopotamia, King Gilgamesh longed to “overcome” death. During the Qin Dynasty, the infamous Emperor Qin Shi Huang was insane about living forever, trying to catch a tiny hope every time there was a chance. This dream of escaping death is an idea still prevalent among people in the world today and is also an idea not too far from being addressed. This article aims to explore Professor Sinclair’s New Theory of Aging that can finally address the question and introduce mechanisms in which this dream can be achieved.
Professor Sinclair’s New Theory of Aging
Professor David Sinclair of Harvard and two co-authors, Yuancheung Ryan Lu and Xiao Tian, published “The Information Theory of Aging” in Nature Aging. In this paper, Professor Sinclair outlines a theory arguing that epigenetic changes are the underlying causes of aging.
What are Epigenetics
Epigenetic changes are heritable changes in gene expression that do not involve changes to the underlying DNA sequence. To provide a layer of flexibility to gene expression, epigenetic regulations are needed. These include DNA methylation, in which the addition of a methyl group (CH3) to cytosine of DNA packs nucleosomes and inhibits transcription (the process of turning DNA into RNA); histone acetylation, in which the addition of acetyl group to certain histone tails unpacks nucleosomes, promoting transcriptions; and chromatin remodeling, in which compact chromatins turns genes off and makes them inaccessible for transcriptions or loose chromatins that turn genes on and makes them accessible for transcription.
However, these epigenetic regulations can be altered by factors such as environmental signals and cellular damage, where aging plays a role.
How does epigenetic regulation involve with aging
According to Professor Sinclair, the loss of the regulatory information discussed above is the underlying cause of aging. In other words, aging causes confusion within the cell due to the wrong regulatory genes being expressed, resulting in other significant changes that should not have occurred. For example, global hypomethylation (reduced methylation levels) can cause aging due to either the relaxation of gene expression regulation and abnormal gene expression.
The Mechanism to Reversing Changes in Epigenetic Regulations
Using the process of embryogenesis for anti-aging mechanisms
Luckily, epigenetic dysregulations are reversible. The foremost example of reversing epigenetic regulations is during embryogenesis. There were a significant number of observations in multiple studies that showed a significant reduction in biological age during the early stages of embryogenesis. This occurs as the cell extends telomeres of chromosomes that shorten with aging during embryogenesis, leading to apoptosis (programmed cell death), oncogenic transformation of somatic cells, or senescence (loss of a cell’s power of division and growth), affecting the health and lifespan of an individual; or rebuilding the epigenome, which are epigenetic regulations that malfunction with age, to avoid damage overload before development.
Usage of induced pluripotent stem cells
A few years ago, scientists were able to mimic this “embryonic reset” through cellular reprogramming. Scientists were able to erase the identity of aged cells and turn them into induced pluripotent stem cells (iPSCs). iPSCs are capable of dividing infinitely to produce new generations of fully functional daughter cells. This allows aged cells to undergo rejuvenation as the protein Zscan4 activation turns on genes involved with telomere recombination (the process by which DNA strands are broken and joined to other strands) when the body senses that telomeres have become too short, a result that causes the aging of cells. As telomere recombination occurs, cells can lengthen their telomeres, allowing them to regenerate the damaged, shortened telomeres and maintain exceptional genomic stability. In turn, the lengthened telomeres allow more cell divisions to occur, which causes cells to produce fully functional, new, daughter cells instead of the damaged ones.
Later, partial cellular reprogramming was developed, in which carefully measured induction of the same factors leads to epigenetic rejuvenation without erasing cellular identity. Both techniques have demonstrated a huge potential in geroscience, extending healthspan and lifespan in various animal models. For instance, a recently covered paper led by Professor Sinclair’s group showed glaucoma (a disease that damages the eye’s optic nerve, often caused by aging) reversal in mice by reprogramming retinal ganglion cells.
Difficulties with reversing epigenetic dysregulation
The unfortunate news is that most living organisms have evolved to accept the loss of epigenetic information. For example, double-strand breaks, which can be caused by radiation or other chemicals, result in both mutations and epigenetic alterations. Both of them are associated with aging, but epigenetic alterations is the one that “causes” aging. In fact, a recent study by Professor Sinclair’s group suggested that DNA breaks cause cellular aging even when they are repaired accordingly. They suggested that this is due to epigenetic alterations that occur during the repair process. For instance, some proteins of the sirtuin family, which plays a double role in guarding the genome and epigenome is known to accumulate epigenetic alterations during DNA breaks as after they repair the DNA, they don’t always go back to their original place, thereby altering their original role.
A positive outlook to address the difficulties using Professor Shannon’s theory
On the bright side, according to the theory, there must be a “backup copy” of the original, pristine state of the epigenome that cells turn to during an embryonic reset, cellular reprogramming, and regeneration events. Here, the theory borrows a lot from Professor Claude Shannon’s information theory of communication.
Shannon’s theory involves an observer who has access to both the information at the source and to the transmission as it was received at the destination, and can correct errors. Professor Sinclair and his co-authors hope to eventually find a cellular analog of this mechanism and have some ideas about how it might work.
In Professor Shannon’s theory, “Passive observers” can be the molecules in our body that act as barriers that prevent changing the epigenetic status of a DNA region that could occur during aging or cellular reprogramming. The expression of the genes guarded by those molecules remains consistent as time passes. “Active observers” are hypothetical molecules that can mark accumulating epigenetic changes for reprogramming factors to roll them back. Understanding those mechanisms would be a major leap for geroscience as they would help scientists better understand how epigenetic changes can be reversed.
Conclusion
Professor Sinclair’s new theory arouses many excitements and hopes for the future of living eternal lives. Although there is much left to uncover regarding the mechanisms of reversing epigenetic dysregulations, much has been discovered and with the development of technology and AI, especially the usage of pluripotent stem cells, many scientists aspire to a bright future with a high possibility of achieving the dream of King Gilgamesh and Qin Shi Huang.
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