File:Expanding Lifespans (50674686032).jpg

In the winter of viral discontent, it might be easy to overlook some recent breakthroughs in lifespan expansion.

David Sinclair from Harvard Medical School just published the latest advances in reversing the biological clock and restoring function in the vision system. Full disclosure: after I read his book, he helped with due diligence when we became the largest investor in <a href="https://www.CambrianBio.com" rel="noreferrer nofollow">Cambrian Bio</a>, a company that seeks to reverse the root causes of aging and disease.

Sinclair’s focus in on analog information loss, the epigenetic noise that accumulates in the methylation patterns running along our DNA and disturbing its expression. This degradation is a biological clock of aging, and today’s results “tell us the clock doesn't just represent time—it is time," said Sinclair. "If you wind the hands of the clock back, time also goes backward."

<a href="https://medicalxpress.com/news/2020-12-scientists-reverse-age-related-vision-loss.html" rel="noreferrer nofollow">Today’s news</a>: “Harvard Medical School scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function. The achievement represents the first successful attempt to reverse glaucoma-induced vision loss, rather than merely stem its progression, the team said. If replicated through further studies, the approach could pave the way for therapies to promote tissue repair across various organs and reverse aging and age-related diseases in humans.

The team's approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction—giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue.

The treatment worked similarly well in elderly, 12-month-old mice with diminishing vision due to normal aging. Following treatment of the elderly mice, the gene expression patterns and electrical signals of the optic nerve cells were similar to young mice, and vision was restored. When the researchers analyzed molecular changes in treated cells, they found reversed patterns of DNA methylation—an observation suggesting that DNA methylation is not a mere marker or a bystander in the aging process, but rather an active agent driving it.”

And from the <a href="https://www.nature.com/articles/d41586-020-03119-1" rel="noreferrer nofollow">Nature Paper</a>: “Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks… Collectively, these changes cause cells to lose their identity and so to lose the DNA-, RNA- and protein-expression patterns that once promoted their youthful resilience. These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo.”

Some of my favorite passages from his recent book, Lifespan:

“Aging, quite simply, is a loss of information. Yes, a singular reason why we age.” (p.20)

“Unlike digital DNA, analog information degrades over time — falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied.” (p.22)

“Our DNA is constantly under attack. On average, each of our 46 chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our body per day. And that’s just the breaks that occur during replication. If we didn’t have a way to repair our DNA wouldn’t last long.: (p.44) “Sirtuins stabilize human rDNA and prevent cellular senescence.” (p.43) “Adding more copies of the sirtuin genes increases the health and extends the lifespan of mice, just as adding extra copies does in yeast.” (p.45).

“Aging itself is a disease. Physicians and researchers have been avoiding saying that for a long time. Aging, we’ve long been told, is simply the process of growing old. And growing old has long been seen as an inevitable part of life.” (p.67).

“We know the process of aging begins long before we notice it. Girls who go through puberty earlier than normal, for example, have an accelerated epigenetic clock. The mistakes are there, even as a teenager.” (p.72)

“Your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.” (p.77) “Though smoking increases the risk of getting cancer five fold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it’s a thousandfold. Such exponentially increasing odds also apply to heart disease. And diabetes. And dementia.” (p.80)

“There’s a reason smokers seem to age fast: they do age faster. Smoking is not a private, victimless activity. The levels of DNA-damaging aromatic amines in cigarette smoke are about 50 to 60 times as high in secondhand as in firsthand smoke. In some places — cities with lots of cars, especially — the simple act of breathing is enough to do extra damage to your DNA.” (p.113)

“NAD boosts the activity of all seven sirtuins. And because NAD is used by over 500 different enzymes, without any NAD, we’d be dead in 30 seconds. NAD acts as a fuel for sirtuins. NAD levels decrease with age throughout the body. Human studies with NAD boosters (NMN and NR) are ongoing. So far, there has been no toxicity, not even a hint of it.” (p.134)

“Once you recognize that there are universal regulators of aging in everything from yeast to roundworms to mice to humans… and once you recognize that these regulators can be changed with a molecule such as NMN or a few hours of vigorous exercise or a few less meals… and once you realize that it’s all just one disease, it all becomes clear: Aging is going to be remarkably easy to tackle. Easier than cancer. I know how that sounds. It sounds crazy.” (p.148)

“Together, all the DNA in our body, if laid end to end, would stretch twice the diameter of the solar system. Unlike a simple DVD, the DNA in our cells is wet and vibrating in three dimensions. No wonder gene reading becomes difficult the older we get; it’s miraculous that any cell finds the right genes in the first place.” (p.159)