The Science of Aging and Longevity

The Science of Aging and Longevity

David Sinclair, PhD is a professor of genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. Generally recognized as one of the thought leaders in the science of how to improve our life span and health span, Dr. Sinclair earned his PhD in Sydney, Australia.

After working with Leonard Guarente at Massachusetts Institute of Technology as a postdoctoral researcher, he got his own lab at Harvard in Y 1999, where he’s been teaching aging biology and translational medicine ever since.

Dr. Sinclair has also written a book, “Lifespan: Why We Age — and Why We Don’t Have To,” which is scheduled for publication on 10 September 2019.

His book covers several important strategies that can help slow down the biological clock, including calorie restriction and intermittent fasting. Two of the scientifically demonstrated benefits of fasting are the suppression of mammalian target of rapamycin (mTOR) and the activation of autophagy.

As noted by Dr. Sinclair, while fasting is not revolutionary, dating back more than 5,000 years, what’s revolutionary “is the discovery of the biochemical pathways that underlie this protection against disease and aging.”

“There are other diets that other people have found to be effective in terms of improving biology and biochemical markers,” Dr. Sinclair says. “One is the 5:2 diet … That one is also quite doable …

More extreme are those diets where you [fast] for a whole week every couple of months or every few months … My view is that that’s probably going to work the best if you can do it, because it doesn’t just trigger the short-term pathways that we’ve been studying in my lab.

A week of fasting will really [trigger] the body to start consuming its own protein … That’s what autophagy is. It’s the consuming of biological material, which is typically protein. In talking with people who’ve done these fasting regimens, after about three days, something different starts to kick in. People who try this tell me that they have a feeling of euphoria. They definitely get an added boost …

We’ve been studying in my lab for the last 20 years genes that respond to diet, to fasting and calorie restriction. The upshot of it is that our bodies respond to adversity or perceived adversity. They turn on these defensive pathways. It changes a bunch of genes that switch on to defend our bodies …

These defenses of the body are extremely good at protecting us against diseases — from diabetes to cancer, heart disease, even dementia and Alzheimer’s. These are things that modern medicine has struggled to combat. This seems to be a very simple way to get the body to fight those diseases.”

As for when to start, animal studies suggest the younger you are when you start, the better. For humans, this would of course have to be done within reason. It would be foolhardy to put an infant on a fasting regimen, for example.

Teens and young adults in their 20’s are also not candidates for fasting, Sinclair says, as “There’s still a lot going on in their bodies and their brains.” After the age of 30, however, extrapolations from animal studies suggest the longer you’re able to incorporate some form of regular fasting across your lifespan, the better.

As a general rule, intermittent fasting involves fasting for 12 to 16 hours a day, which will typically necessitate eliminating either breakfast or dinner. If you eat dinner, you will want to make sure you do it early enough, at least 3 hours before bedtime.

One of the reasons for this is because avoiding late-night eating will increase your nicotinamide adenine dinucleotide (NAD+) levels, which are important for a variety of bodily functions.

Importantly, it will also reduce nicotinamide adenine dinucleotide phosphate (NADPH), which is essentially the true cellular battery of your cell and has the reductive potential to recharge your antioxidants. The largest consumer of NADPH is the creation of fatty acids.

If you are eating close to bedtime, then you are not going to be able to use the NADPH to burn those calories as energy. Instead, they must be stored some way. To store them, you have to create fat, so you’re basically radically lowering your NADPH levels when you eat late at night because they are being consumed to store your extra calories by creating fat.

“I tend to snack at night, so it’s my downfall,” Sinclair says, “but yes, to be able to have that fast overnight, that’ll boost your NAD and NADPH levels. These are all good things. They turn on the enzymes that we study called sirtuins. They need NAD to function. You can use the whole night to ostensibly repair your body and protect it from what happens during the day.”

One of the most fascinating aspects of Dr. Sinclair’s book is the section on how to resolve some of this epigenetic damage, which accumulates through aging.

Using the clustered regularly interspaced short palindromic repeats (CRISPR) technique, certain transcription factors were spliced into blind mice, thereby restoring their vision through epigenetic resurrection.

Dr. Sinclair explains:

“This is a sneak preview of what, hopefully, will be published later this year … We’ve discovered what we think is very strong evidence for … epigenetic noise as a cause of aging … What does that mean?

Let’s just quickly do a biology lesson for those who haven’t been in high school for a while … [The] epigenome is the organization of DNA. The epigenome tells the cell that they should turn on this gene to be a nerve cell, and in a liver cell … Cells inherit that [epigenetic] information just as much as they inherit their DNA.

In my book, what I’m proposing is that … genomic and epigenomic information are quite different. The genomic, the DNA, is ‘digital,’ which is very well-preserved and can last a long time. We know that DVDs last longer than cassette tapes.

The problem for the epigenome is that it’s ‘analog’ information. Anyone who’s had a cassette tape or a record knows that you can pretty easily scratch these or lose the information. You can [also] scratch a DVD and lose the information.

We think aging is similar to those scratches; that the information to be young again is still largely in our bodies. Our cells can access that information by metaphorically polishing the DVD … so the cell can read the right genes …

With that in mind, let me explain what we’ve discovered. We have a metaphorical way of scratching a mouse’s epigenome: We cut the DNA. We create these double-strand breaks [and] let the cell heal … so there’s no change to the digital information. But what we see is the process of proteins moving around and trying to repair that DNA.

It eventually introduces this epigenomic noise, and the genes that were once on, many of them get turned off. Those that were once off come on. Liver cells start to lose their identities. Skin cells start to lose their identity. The consequence, we think, is aging.

We will hopefully publish a paper that shows that if you create this noise in a mouse, it will go through accelerated aging … Second of all, we have mice now that we can change the rate of aging in … The third thing is if you can give an animal something, then you can, with that knowledge, take it away. That’s what we’ve done …

We wanted to reprogram cells. The genes that were … on, now they go back off and vice versa … What we find is that by using these three Yamanaka factors, you can find the original information in the cell that tells it to be young again.

Those genes switch, and the cell behaves like it’s young again. In the case of the retina, we have preliminary results [showing] we can restore eyesight by rejuvenating the nerves in the retina to be young again.”

Dr. Sinclair’s goal is to identify ways to reprogram all cells in the body, such that they not just act younger but literally are younger on a molecular level. “In my career, I’ve seen a lot of cool stuff. I haven’t seen anything this cool before,” he says. Clearly, there’s extraordinary potential to extend the human life span beyond the current 120 anni limit.

In his book, he proposes there’s no built-in biological requirement for death, and that, theoretically at least, you could live hundreds of years, as he explains in this video.

To learn more about Dr. Sinclair’s research, and the science behind aging and the potential for reversing aging, be sure to pick up a copy of his book, “Lifespan: Why We Age — and Why We Don’t Have To.”

“We could see a world where people do choose to be genetically modified,” Dr. Sinclair says. “It’s their choice, right? I don’t think we can easily go in and modify children even though that’s now being done, unless it’s life-threatening, of course. But adults know that they should be able to have a choice if they’re safe and it’s approved, then they should be able to do that.

Maybe there will be a day when we are able to carry these Yamanaka genes in our body. And when we get sick or we have an injury … then we get an IV that turns on those genes for a month. We recover and rejuvenate, then we turn them off again until we need them again. That would be a pretty wild sci-fi future, but both signs are pointing to at least the biology being possible …

I hope people who read the book come away with a new view of what’s possible. Some people who have read it tell me that it’s changed the way they look at their own lives. That’s what I wanted to do. I think we forget how important this topic is, that we can do things right now to alter the course of our lives.”

Eat healthy, Be healthy, Live lively

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