Altering Metabolism to Slow or Override Aspects of Aging

Below find linked a popular science article on some of the strands of research that aim at safely altering the operation of cellular metabolism to either (a) gently slow aging by reducing the pace at which underlying cell and tissue damage accumulates or (b) override some of the reactions to cellular damage that cause declines in tissue maintenance. Neither strategy aims at repair of that damage, unfortunately, and so is ultimately limited in the quality of results that can be achieved: no true rejuvenation, no indefinite healthspan, just a slowing of the inevitable. Nonetheless, overriding natural mechanisms to restore age-related declines in stem cell activity seems to be on track to produce benefits despite the continued presence of unrepaired cell and tissue damage. The evolved balance between cancer risk and stem cell decline appears to leave more room for action than anticipated.

The majority of older Americans live out their final years with at least one or two chronic ailments, such as arthritis, diabetes, heart disease or stroke. The longer their body clock ticks, the more disabling conditions they face. Doctors and drug companies traditionally treat each of these aging-related diseases as it arises. But a small group of scientists have begun championing a bold new approach. They think it is possible to stop or even rewind the body's internal chronometer so that all these diseases will arrive later or not at all. Studies of centenarians suggest the feat is achievable. Most of these individuals live that long because they have somehow avoided most of the diseases that burden other folks in their 70s and 80s. Nor does a centenarian's unusual longevity result in an end-of-life decline that lasts longer than anyone else's. In fact, research on hundreds of "super agers" suggests exactly the opposite. For them, illness typically starts later and arrives closer to the end.

Living longer may come with trade-offs. Making old cells young again will mean they will start dividing again. Controlled cell division equals youthfulness; uncontrolled cell division equals cancer. But at the moment, scientists are not sure if they can do one without the other. Figuring out the right timing for treatment is also complicated. If the goal is to prevent multiple diseases of aging, do you start your antiaging therapies when the first disease hits? The second? "Once you're broken, it's really hard to put you back together. It's going to be easier to keep people healthy." So it probably makes more sense to start treatment years earlier, during a healthy middle age. But the research needed to prove that supposition would take decades.

If various diseases can be pushed off, the next obvious question is by how long. It will take at least another 20 years of study to answer that question. Scientists have successfully extended the life span of worms eightfold and added a year of life to three-year-old lab mice. Would these advances translate into an 80-year-old person living five or six centuries or even an extra 30 years? Or would they get just one more year? Life extension in people is likely to be more modest than in yeast, worms, flies or mice. Previous research has suggested that lower-order creatures benefit the most from longevity efforts - with yeast, for instance, deriving a greater benefit in caloric-restriction experiments than mammals. The closer you get to humans, the smaller the effect on life span. And what magnitude of benefit would someone need to justify taking - and paying for - such a treatment? "Do you take a drug your whole life hoping to live 4 percent longer or 7 percent longer?"

I would hope that question never arises in any practical sense for the population at large, as efforts to alter metabolism to slow aging should be quickly overtaken and discarded in the near future by the far better results I'd expect to see achieved through damage repair therapies, such as those proposed in the SENS programs. SENS-like rejuvenation approaches based on repair of cell and tissue damage are slowly advancing to the point of generating meaningful results. That is already the case for senescent cell clearance, but there are numerous other lines of rejuvenation research still at far earlier stages. The sooner this transition happens, the better off we all are.

Link: http://www.scientificamerican.com/article/researchers-study-3-promising-anti-aging-therapies/

Comments

What the article mentions about the length of trials and studies is what concerns me. Even if a way to reverse some of the damages caused by aging was figured out in 2020, I'd assume that we wouldn't see anything until 2035 at the very least... unless it was via medical tourism. Maybe. As much as we'd all like it to happen, I don't know if the SENS type approach is going to overtake the tinkering with metabolism approach anytime soon. That's what the majority of scientists know and are used to. I'm pumped about the senescent cell clearance, and I hope something really comes of it though.

Posted by: Ham at July 27th, 2015 7:39 AM

The time it takes to get research to trials and the cost is broken. I believe we will see promising technology taken abroad (this is already happening) and used years or even decades before the FDA approves it.

The Conboy lab has produced meaningful rejuvenation of various tissues and stem cells woken up from dormancy repair damage. It has been demonstrated that DNA damage such as double strand breaks are no longer visible in stem cells having been rejuvenated. This has been observed by the Conboys. Messing with metabolism is complicated but going as far upstream as possible to deal with the root of those changes is a viable approach. Having read the Conboy work and spoken to them at length I personally feel their approach could work. They use a small amount of pathways to produce good results without getting lost in the complexity of downstream pathways. So far their results have worked in brain, muscle, bone and skin cells and tissue, Irina and Michael are hoping this effect is a common mechanic and thus a suitable point of intervention. Another intervention point is the telomere according to Dr Michael Fossel.

I have heard people say that rejuvenating the stem cell niche is returning damaged stem cells to work but based on what Irina has said that is not the case, the stem cells once mobilized rapidly repair the damage, indicating that either the cell is perfectly able to repair said damage when given the right signals or that the damage was not significant in the first place. There are studies showing neonatal stem cells (admitedly not aged SCs) allowed to enter Senescence can be rescued in a similar manner and DNA strand breaks observed in the cells were absent once the SC was rejuvenated.

The Conboy work addresses a number of underlying reasons for aging including functional and regenerative decline, apparently their technique resets telomeres too addressing genomic stability somewhat, it has also been shown to improve gene expression profile (Confirmed that TGF-b1 and B2M levels return to near youthful expression after treatment and likely other genes) which again contributes to genomic stability and of course improves replication of the stem cell and also addresses stem cell depletion.

I often hear this work does not address the underlying causes of aging but clearly it addresses certain underlying aspects as well as addressing functional decline and tissue damage. This paper shows for example that DNA damage in HSCs is due to a decline in repair mechanisms:

http://www.ncbi.nlm.nih.gov/pubmed/24813857

Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. Rejuvenating stem cells to repair and boost tissue damage response as well as reducing inflammation levels is going to help matters.

Recently Irina said they could have a working and potentially systemic rejuvenation therapy in ~5 years this would include phase 1 clinical apparently. This is probably one of the few therapies I can see being even remotely near future plausible.

Posted by: Steve H at July 29th, 2015 6:09 AM

I hope their therapy does progress and make it through clinical trials. Even though it likely won't be the end all treatment, if it buys more time for people than its a win I think. But my concern if it gets through trials and brought to market would be the cost... But I suppose that's something to worry about after it passes trials.

Posted by: Ham at July 29th, 2015 7:27 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.