LEAF Interviews David Sinclair

David Sinclair recently published a new book to assist in publicizing his present research directions, companies, and thinking on aging, and is here interviewed by the Life Extension Advocacy Foundation (LEAF) volunteers. The work presently underway includes supplements to increase levels of NAD+ in mitochondria and, separately, partial reprogramming of cells in a living individual in order to gain some of the effects of full reprogramming, particularly restoration of mitochondrial function. Fully reprogramming cells into induced pluripotent stem cells has been shown to clear out dysfunctional mitochondria and reset epigenetic markers of age to a more youthful configuration.

It is worth noting that this strategy will not be able to fix a great many of the issues that arise in cells with age, such as the accumulation of metabolic waste that even youthful cells cannot break down effectively. If it can be used to safely restore mitochondrial function in old tissues for an extended period of time, however, then that is certainly interesting enough to chase aggressively in and of itself. Mitochondrial dysfunction is a noteworthy aspect of aging, and is involved in numerous age-related diseases.

Currently, medicine treats the symptoms, not the causes, of age-related diseases. Do you think that we might soon reach the point where therapies will be taken in a preventive manner to delay the onset of age-related diseases?

Well, there's a subset of the population, particularly in the US, but increasingly around the world, who are using the internet to educate themselves and are trying to take action before they become sick. Sometimes with medical supervision, sometimes not. It's a grassroots movement right now; for it to become mainstream, the regulations would have to change so that doctors can feel comfortable prescribing medicines to prevent diseases. But, if we don't change, then we will continue to practice whack-a-mole medicine and only treat one disease at a time after it's already developed.

You are very well known for your work with NAD+ and its precursors; we're often asked whether nicotinamide riboside or nicotinamide mononucleotide is better?

They're very similar molecules, and both have been shown to provide a variety of health benefits in mice. That doesn't mean either of them will work to slow aging in humans, and that's why placebo-controlled clinical trials are required to know if one of them, or both of them, will work in certain conditions. Those studies began over a year ago, and they are currently Phase 1 safety studies in healthy volunteers. Next year, the plan is to test the pharmaceutical product in a disease area, most likely a rare disease, but also in the elderly to see if we can recapitulate some of the results we've seen in mice, such as increased blood flow and endurance.

Another area that you are involved in is partial cellular reprogramming to reverse age-related epigenetic alterations in cells and tissues. Please tell us a little bit about this approach and the approach that you are taking and how you're progressing so far?

For 20 years, we've been working on epigenetic changes as a cause of aging, starting with work in yeast and now in mammals. We've developed viral vectors and combinations of reprogramming factors that appear to be much safer than past approaches, and we've used them to reprogram the eye to restore vision in mice with glaucoma and in very old mice. Currently, it is believed that the epigenetic clock is just an indicator of age and not part of the actual aging process, but our recent work strongly suggests that the process of reversing the clock doesn't just change the apparent age of the body, it actually reverses aging itself by restoring the function of the old cells to behave as though they're young again. Therefore, the clock may not just be telling time; it may actually be controlling time.

Could you please tell us a little bit about your book and what the readers should look forward to?

"Lifespan: Why We Age and Why We Don't Have To" takes the reader on a journey through history, looking at the endeavor of humans to try to live longer and using that historical perspective to look at today's situation and project into the future. The book also takes readers on a journey through the very cutting edge of aging research and things that the reader can do right now to take advantage of these new discoveries in their daily lives with changes in their daily activity, what they eat, when they eat, but also medicines that are currently available on the market that may extend lifespan. The last chapter is about where we are headed, what are the medicines that are in development, and then when these drugs become available, what does the world look like? Is it a better place or a worse place, and how will our lives change?

Link: https://www.leafscience.org/an-interview-with-dr-david-sinclair/

Comments

Obviously an extremely smart guy

But the Life Bioscience model (like Juvenescence) to create a "mini conglomerate" of anti-aging companies is as stupid as they come

At the end of the day in this "pseudo-VC" model portfolio companies eventually start to cannibalize each other

Better off putting the majority of your funding into a few of the most promising projects

Posted by: David Permisov at September 12th, 2019 6:32 AM

"It is worth noting that this strategy will not be able to fix a great many of the issues that arise in cells with age, such as the accumulation of metabolic waste that even youthful cells cannot break down effectively."

you make continuously lots of claims, most of them are pure speculations with no relation to real research.

can you provide studies that support your "worth noting" from above.

Posted by: m&m at September 12th, 2019 11:09 AM

"It is worth noting that this strategy will not be able to fix a great many of the issues that arise in cells with age, such as the accumulation of metabolic waste that even youthful cells cannot break down effectively."

With all due respect, this sounds like a personal opinion and not established scientifc fact. I have a great deal of respect for you as a colleague reason but you are jumping the gun here.

Posted by: Steve h at September 12th, 2019 11:32 AM

I also have nothing but respect for Reason; he's one of the smartest and most passionate people I'm familiar with, but I agree with Steve that it might be too early to say how significant of an impact this strategy will have on biological age-related damage.

Posted by: Quinn at September 12th, 2019 11:39 AM

Come on; those of you who think there is a possibility that reprogramming a cell will allow it to break down molecules that a young cell or an embryonic stem cell cannot break down, or repair nuclear DNA damage that a young cell or embryonic stem cell will not repair, please do propose a mechanism by which this could possibly occur.

If we are reprogramming in vitro, I'll grant that asymmetric division can extract you from a number of problems, in theory, but not if we're talking about partial reprogramming in vivo in which the goal is to improve the cell, not turn it into an induced pluripotent stem cell.

Posted by: Reason at September 12th, 2019 11:50 AM

I wouldn't be surprised if you're right, Reason, but ultimately, the data will provide the true result, as we all know.

Posted by: Quinn at September 12th, 2019 12:14 PM

Reason is correct (so long as the current model of irreparable aging byproduct accumulation is complete, and no hidden cellular capacity of youth has escaped the field's notice). His statement does rest on top of mountains of data, however. There is "jumping the gun", and then there is making a theoretically and empirically-tight limiting of expectation.

Posted by: Ted at September 12th, 2019 1:13 PM

@Reason

"Come on; those of you who think there is a possibility that reprogramming a cell will allow it to break down molecules that a young cell or an embryonic stem cell cannot break down, or repair nuclear DNA damage that a young cell or embryonic stem cell will not repair, please do propose a mechanism by which this could possibly occur."

There are clearly some metabolic waste products and damage for which the human body has absolutely no recourse, the best candidates being alterations to long lived proteins in the ECM and compounds that accumulate in long-lived cells, and of course base pair level damage to DNA, which is an indisputable example of damage that's intractable when it occurs in an irreplaceable cell,, that clearly must happen to some extent.

Ultimately we don't actually know how extensive that kind of irreversible damage is versus damage that the body can in principle repair but doesn't in old age. One potential example of this is elastin; damage to elastin appears to have an even greater impact on loss of tissue elasticity during aging.

Evidence suggests that the body is in fact capable of replacing damaged elastin during development, and yet it fails to do so later on in life, with biosynthesis and active maintenance of elasitn slowing rapidly after development and ending completely by middle age. There's also potentially forms of damage that the body can and does repair actively that it fails to keep up with; many amyloids could fall into this category.

I do not believe we have sufficient understanding of the underlying biochemistry to claim with confidence that we know to what extent the different kinds of damage (intractable, unresolved, and inadequately addressed) are dominant in the development of the aging phenotype and the parthenogenesis of age related diseases in humans.

The answer to this question has major significance for what avenues of therapy we should be pursuing; the SENS is the clear winner for any damage which is totally intractable within the context of human biochemistry. In cases where you can achieve this without unacceptable risks of cancer, re-activation of developmental pathways would work for damage that is repaired during development but not later life. Meanwhile, slowing the rate of accumulation of damage that the body fails to keep up with to below whatever threshold could halt or even reverse its accumulation.

My own suspicion is (and you can call me a conflict-averse, non-committal coward if you want) that all three categories of damage kinetics probably exist in vivo and contribute to the overall process of aging. Consequently there may be space for all of the proposed approaches to intervention in human aging to coexist, along with conventional disease focused medicine; while many could be useful adjutant therapies, none of the proposed approaches for addressing aging seem capable of treating someone who current has cancer, and that may be true for other age related disease states.

Posted by: Dylan Mah at September 12th, 2019 2:22 PM

I will re-post my thoughts per the last time this debate popped up a week or so ago in the AgeX "unified theory" post:

Just to shine some extra light on this question / discussion as it gets a but confused at times

There is a bit of difference between cellular reprogramming and whole organism reprogramming

The former, per the technologies of AgeX, Turn, Salk, etc., are tools for in essence "cleaning up a cell" - epigenetic modifications, organelle remodeling, telomere "re"-longation, etc.

These are all variants from the original 1952 cloning experiments by Robert Briggs and Thomas J. King, modified by Gurdon, Jaenisch, Yamanaka, and many others etc. into the current day - and they are all pretty good, from one angle or another, in making a cell "younger / rejuvenated "

The latter, organism rejuvenation via reprogramming, is a bit more complicated, but can be summed up as such:

Organisms (such as amphibians, planarians, echinoderms, hydrozoans, etc.) that have the ability to "turn back biological time", to regenerate / repair / rejuvenate most (or all) of their bodies, possess two inherent capabilities that they use in synergy: 1) The ability to re-establish the "embryogenic" potential of their cells / genomes / gene regulatory networks (per inherent cellular reprogramming dynamics - like above),

AND, of equal, if not greater, importance,

2) ...the ability to re-establish the "morphodynamic" architecture of their tissues / organs / limbs / body segments

The latter involves many other things beyond cell reprogramming - ECM remodeling, activation of the innate immune response, membrane potential changes, and a long additional list of other stuff that I won't take up space with here

But the point is, it is in the context of the regenerative micro-environments that RESULT from this reprogrammed cellular flexibility that we see the really neat stuff happening - not just in these "lower" non-human species, but also in mammalian embryos - this is why you can "dump" all sorts of "junk" into a mammalian embryos (somatic tissues, viruses, cancer cells, etc.) and it all gets organized out

Here are some links to nice reviews on the general theme of regenerative micro-environments and their ability to organize in / out stuff they don't need, and well as modify the diseased phenotype. As a subset of this re-organization theme, here are also papers on the topics of revertant mosaicism (primarily seen in tissues with an active regenerative niche) and cellular competition (seen in both development and the maintenance of tissue fitness)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735296/pdf/v040p00721.pdf

http://jcb.rupress.org/content/200/6/689.full

The seminal work on embryos and teratocarcinoma was done by Mintz et al in Philadelphia in the 1970s:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC433040/

Similar dynamics also occur in the plant kingdom:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC335936/

The point is that for whole organism human rejuvenation using such tools, especially for complex tissues and organs, we will need to go beyond just throwing in reprogramming factors and walking away

But there is tremendous potential with these tools if used correctly in the right bio-dyanmic context

Posted by: Ira S. Pastor at September 12th, 2019 2:46 PM

I wouldn't criticize Reason for his assumption epigenetic reprogramming will not be the golden bullet, that seems obvious, I would criticize him for sticking loss of epigenetic information in the SENS dysfunctional mitochondria box. Loss of epigentic information is probably the 8th deadly sin ähhh SENS.

Posted by: Tom at September 12th, 2019 9:30 PM

I just finished David's book and it was excellent. I was very pleased to see that he discussed other anti-aging technologies being studied besides his own research. He talked about senolytics, metformin, as well as Rapalogs, etc. His book has given me a clearer overall picture about how theses things might work. A must read for the casual student of anti-aging science but even his most brilliant research peers should find something of value here and there. It is extremely well written, not dry, and understandable enough to share with those who may not yet be as enthusiastic as we all are.

Posted by: August at September 19th, 2019 7:00 PM

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