Is Aging Inevitable?

“I refuse to accept that aging is something we have to live with.”

David Sinclair opened his recent talk entitled “Cracking and reversing the aging clock,” with this phrase — among other age-defying (age-denying) quotations.

This isn’t an uncommon utterance from Sinclair, who is a prominent scientist in the field of aging biology. Sinclair runs a lab at Harvard, was previously at M.I.T., and has been a featured guest of many podcasters including Joe Rogan and Peter Attia. His publications have been a hot topic in the scientific as well as popular media. In fact, you can “blame” his discoveries for the now popular (mis)conception that “red wine is good for you.” Indeed — Sinclair was one of the first researchers to show that resveratrol (a compound found in red wine) extended the health and lifespan of mice fed a high-calorie diet.

Now, Sinclair mainly focuses on ways to extend human lifespan. In fact, he’s pretty obsessed with the idea of living to be 150 years or older. Or rather, he’s afraid of dying. Whatever his motivation, the research he’s doing seems promising, and he’s well equipped to advance the concept of human aging away from preconceived notions. Lifespan, it seems, is hackable.

Technology for reducing human aging and extending human lifespan might be just around the corner.

As we begin to better understand the actual causes of aging (something Sinclair has contributed hugely to), we become closer to developing ways to address it. But, without a true “unifying cause” it is unlikely that a treatment or treatments will prove to be successful. There is likely more than one cause of aging. Whether diet, exercise, and genetics are involved, and to what percent, is a mystery.

One proposed “root cause” may be the loss of information in the body. This is a rather new hypothesis proposed by Sinclair in his recent talk. The “information” under discussion is DNA and the bases that code it. Sinclair relates this genetic information to a CD. Throughout life, we accumulate “scratches” on the CD — that’s DNA damage.

In addition, epigenetic changes to DNA result in a “loss” of the more youthful DNA, replacing it with certain markers that are associated with aging. From the second we are born, our lives and our DNA have moved in a unidirectional path. Aging starts in the womb.

But what if our body retained a copy of our stored information — a “backup” of our younger DNA from a time before the epigenetic changes and DNA damage occurred. And, if we do have this backup information stored, what if we could somehow access it, “turn it on”, and reverse age-related changes in our genes — maybe reverse aging itself?

A new publication from Sinclair and colleagues addresses this hypothesis.

Titled “Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming”, the paper proposes that a new method, aptly termed REVIVER, may have the potential to reprogram genetics, reverse the “scratches” on our genetic CD-ROM.

The study tackles genetic decline from the angle of the previously mentioned “information theory of aging” which proposes that a loss of our epigenetic information is what really disrupts the youthful patterns of gene expression that keep us free of disease and decline. Changes in genes can lead to cell dysfunction and senescence (a cell that no longer “works”) and therefore aging.

In particular, these genetic changes involve something known as methylation — a process by which “methyl” groups are added to DNA, altering its normal function. Methylation is associated with aging, but whether it’s a cause or effect is currently unknown.

Resetting epigenetic marks like methylation could be the key to reverse aging. One way to do this is by expressing DNA transcription factors known as “Yamanaka factors” (heretofore referred to as OSK). Yamanaka factors (named for the scientist who discovered them) are able to reprogram cells into stem cells — essentially “resetting” their accumulated genetic changes and allowing them to develop into new cells types (this is called pluripotency).

Yamanaka factors may be one way to access the “backup” epigenetic information stored in mammalian cells. If possible, perhaps we can reverse a host of age-related deficits caused by dysregulated genes. That’s the hypothesis of the paper…at least.

Testing the hypothesis required a series of elegant experiments, which I’ll only briefly cover below.

First, Yamanaka factors were introduced into fibroblast cells isolated from old mice to test their effect on levels of RNA known to be altered or involved with the aging process. Treatment with the Yamanaka factors promoted more youthful gene expression patterns in the cellular RNA.

Next came testing in an actual live mouse (in vivo experimentation). Here, the system of interest was the central nervous system (CNS). This was chosen because this is one of the first systems to its regenerative capacity with age. Certain cells within the CNS, called retinal ganglion cells (RGCs) project nerve cells from the retina toward the brain, forming the optic nerve.

Just a few days after birth, RGCs lose their ability to regenerate and their function starts to decline. This is perhaps one reason why we lack the ability (so far) to restore eyesight.

But maybe RGCs retain their regenerative capacity, and just need to access the genetic information responsible for it. To test this, the scientists damaged the CNS by crushing the optic nerve of adult mice prior to and after induction of Yamanaka factors. When OSK expression was induced after the optic nerve injury, there was a significant improvement in axon regeneration and greater survival of the RGCs.

Images of the optic nerve at 12- and 16-weeks post crush with (OSK) and without Yamanaka factors.

What was “responsible” for the protection? Measuring “epigenomic age”, it was shown that the Yamanaka factors were able to “preserve” a younger epigenome. The optic nerve cells from untreated mice showed accelerated aging of their epigenome. The treated mice were protected from this aging effect. When the same model was used in older mice (12 months vs. 4 months), similar promising results were shown.

Mice data are cool. But what about humans? Is neuronal reprogramming applicable — no, possible — in humans? The same Yamanaka factors were introduced into cultures of human neurons, neurons which were then “degenerated” using a toxic chemotherapeutic agent. After just 9 days of recovery, the DNA methylation “age” was increased in neurons without treatment, while those receiving OSK were not only protected from the damage, but showed a “younger” DNA methylation age. A 15-fold greater neuronal area was present in OSK-treated cells vs. those receiving the control treatment.

A potential application for all of this fascinating research is glaucoma —a disease that involves a progressive loss of retinal ganglion cells due to, among other factors, increased pressure in the eye. Glaucoma is the leading cause of age-related blindness in the world, and no current treatment exists. Once vision is gone, it’s gone…for now.

Using REVIVER for 4 weeks, increased the axon density and visual acuity in a mouse model of glaucoma.

In fact, OSK restored about half of the age-related vision loss in mice, a result attributed to an increased function of the retinal ganglion cells.

When REVIVER was used in old mice without glaucoma, the age-related loss of vision was completely restored to that of younger mice.

Scatter plot of OSK induced changes versus age-associated changes in mRNA levels of genes involved in aging

This is the first treatment to reverse vision loss in an animal model of disease.

Many conclusions can be made from this study. For the first time, reprogramming of aged neurons was shown to essentially reverse age-related changes in DNA, partially or sometimes completely restoring “youthful” function.

Mice (and perhaps human) cells may actually retain their youthful capacity in some sort of metaphorical “backup disc.” This is a pretty cool concept. It suggests that sure, we all age, but somewhere within our genome may be hiding our “younger’ selves. How, where, and why we retain this more youthful DNA pattern is unknown, but is likely a topic to be explored in the near future.

Vision may just be the starting point for an exploding area of research. Given the promising results shown in this study, it’s now time to explore the potential of techniques like REVIVER to give other complex human tissues an enhanced ability to recover from injury, restore their function, and perhaps resist the age-related decline in structure and function that, while once seen as inevitable, may soon be “optional.”

During the same talk, Sinclair asked the audience; “how many of you would like to live to be 120?” About 1/3 of the listeners raised their hands.

Rephrasing the question, Sinclair asked; “how many of you would like to live to be 120 if you could feel the way you do now.”

The entire audience raised their hand.

Perhaps one day, this far-fetched notion will become a reality.

References

Yuancheng Lu, Anitha Krishnan, Benedikt Brommer, David A. Sinclair. Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming.bioRxiv 710210. https://doi.org/10.1101/710210

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PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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Brady Holmer

Brady Holmer

PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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