Regenerative Medicine and the Future of Healthy Longevity
One of the many possible future banners for applied longevity science is to call these treatments capable of extending healthy life span simply "regenerative medicine." In past years, regenerative medicine has referred to the output of the stem cell research community: ways to manipulate and transplant cells in order to create regrowth and healing to a degree that would not normally occur. But why not broaden the usage to include repair of damage within cells, and removal of metabolic waste in tissue structures between cells? It isn't such a leap. The stem cell research community is presently largely focused on building treatments for the old, and thus these researchers will have to solve many of the issues affecting old cells one way or another in order to render their therapies effective.
Looked at this way, "regeneration" and "rejuvenation" are really not so different in meaning. Aging is a matter of accumulated damage that is beyond the capacity of the body to heal, and regenerating old tissue by removing some that damage might as well be called rejuvenation. Such a treatment would remove some of the differences between old tissue and young tissue, and would aim to restore function to a point closer to that of a youthful, healthy individual. In isn't hard to think of aging as an illness, a progressive medical condition, when looking at things in these terms, and that seems to me to be a good viewpoint on the situation if it inspires more people to help do something about it.
Here is an enthusiastic two part piece that mentions regenerative medicine, advanced research such as the SENS programs, as well as other work on immunotherapies and clearance of senescent cells. All of this is in the context of looking ahead to the near future of new therapies and improvements in maintenance and restoration of human health:
Can Regenerative Biotechnology Extend Our Productive Lives?
"It's obvious to me that university laboratories can't do it alone," says University of Southern California professor of gerontology and biological sciences Caleb Finch. "Big Pharma can't do it alone. A marketplace of ideas has to be developed. Those of us who come to these meetings have an increasingly broader set of professional alliances. You get a high table of very smart people around you who represent different disciplines and technologies.""Disease-modifying cell therapy is very quickly becoming a reality," declares Stephen Minger, chief cellular scientist at GE Healthcare in the United Kingdom. "We're all piling on this now. Until recently, pharma and biotech had no interest in the field - now everybody and his brother is setting up a cellular therapy program. There are a lot of Phase I and Phase II trials under way, with patients getting benefits. We're progressing very rapidly. A lot of money is being pumped in."
"Chronic diseases of aging account for the vast majority of health care expenditures," points out biochemist Judith Campisi, of Lawrence Berkeley National Laboratory and the Buck Institute for Research on Aging in Novato, Calif. "Traditionally, medicine has dealt with them by specializing. But people who study cancer, or neurodegenerative diseases like Alzheimer's, or painful osteoarthritis, or chronic obstructive pulmonary disease or congestive heart failure ... they don't talk to each other. The evidence in medicine is growing, however, that old age is malleable. It may not be inevitable. There are underlying basic processes, and if we could intervene [at that level], no longer treat [separate diseases] but treat aging processes like cellular senescence, it would totally transform medicine." Campisi has been experimenting with a recombinant drug that successfully flushes senescent cells from elderly transgenic mice - a far cry from proving efficacy in humans. And even the lifetime of these mutant lab mice is extended by only another 20 to 25 percent, she notes.
The Big Breakthrough in Rejuvenative Medicine
Immunotherapy is a revolutionary "personalized" medical technique by which blood is harvested from a patient; and the genetic machinery of its T cells - the body's potent main defense against most pathogens but normally unreactive to cancer cells - is altered by introducing an inactivated, genetically modified HIV virus. The souped-up blood is reinfused. The patient's own T cells now can detect signature proteins on the cancer cells and swarm to destroy them.Several immunotherapeutic approaches such as chimeric antigen receptor therapies are under active investigation for a variety of cancers. Results in initial trials have been highly encouraging - in some instances, astonishing. Moreover, notes Stephen Minger, major pharmaceutical companies and niche startups are "piling on this now." "Individualized cell therapy is at the inflection point," he maintains. "It's going to change fundamentally the way we treat cancer ... [but it also holds promise for] orthopedic indications, repair of bone and cartilage ... organogenesis ... autoimmune diseases like multiple sclerosis, lupus, inflammatory bowel disease and Crohn's disease, where there's been very little therapy available and patients are sick all the time and in a lot of pain ... .
"We're starting to see clinical benefits from targeted immune therapies that spare normal tissue and are completely curative," he summarizes. "It's not just a niche. We're looking at treating very large patient populations to whom we've had very little to offer before. Now we have to address how to deal with millions of them a year. There's a huge amount of excitement around this. We're all ecstatic. But the hard stuff is ahead of us. It's going to be totally, totally disruptive."
Hold on - "Campisi has been experimenting with a recombinant drug that successfully flushes senescent cells from elderly transgenic mice - a far cry from proving efficacy in humans. And even the lifetime of these mutant lab mice is extended by only another 20 to 25 percent, she notes."
That is quite big news buried in there that Judith Campisi and the Buck Institute have a small molecule drug candidate that selectively removes senescent cells in an animal model, and then extends the lifespan of these mice by 20 to 25% versus controls.
Personally I was always suspecting/fearing that protein and gene targets in senescent cells would be 'undruggable' by small molecule drugs and would require the use of T Cell Receptor like antibodies (TCR Like Antibodies) targeting protein fragments from protein targets presented via the HLAs on the surface of senescent cells. A small molecule drug could be a lot simpler and cheaper.
Actually re-reading that article the word "transgenic mouse" is now jumping out at me. The author of the article is probably just confusing the Buck Institute's search for a small molecule drug with the Mayo clinic's use of a transgenic mouse whose senescent cells can be easily removed, and which is not applicable as a therapy in humans.
Hey Jim - Do you know what changes exist in the transgenic mice the Campisi lab is using?
And is there a potential future in the use of, say, CRISPRs to insert genes that would allow us to use small-molecule drugs to induce apoptosis and/or immune targeting of cells that are senescent or pre/cancerous?
Jim - Does the work on beta-galactoside capped nanoparticles counts as a small molecule-based intervention? If so then this seems a viable route that is being pursued. But yeah, that was the part of the article that jumped out at me, especially since a senescence-clearing strategy seems to be near-term possible and likely rather beneficial.
Reason - Do you know if the author is wrongly attributing information about Campisi's work? It would be rather disappointing to me if complete removal of senescent cells gives lifespan extension benefits similar to calorie restriction (this is the claim in the article that I most care about).
I am just a layperson with an interest in all of this. I have no more idea of what is going on in these labs than anyone else reading these articles.
@Seth - I'm guessing that transgenic means that an extra gene has been inserted into the mouse's genome via germline (fertilized egg) genetic engineering. The Mayo clinic did that so that when the P16 gene associated with senescence activated, half of a protein drug was also created in said cell. Administering the other half of the protein drug then killed those P16 senescent cells. I have no idea whether you could use CRISPR to genetically engineer every cell in the body of an adult. Probably more likely is that a small molecule drug or nanoparticle like Gheme mentioned would be practical. TCR Like antibodies are another possible means of culling senescent cells. These are being developed for use against proteins that only cancer cells make. They are not yet in clinical trials from what I have read.
@Gheme - from my limited undergrad level knowledge a small molecule drug is just a simple chemical or small molecule that can easily pass through cell membranes into cells. Antibodies and nanoparticles are much larger structures.
Such genetic manipulation would work on humans, the problem is we're nowhere near good enough at delivering genetic material to cells. When we get to the level when we can reliably deliver genetic material to every cell in the body, selectively killing senescent cells will be pretty trivial, but we're a long way from that point, and in the short term other methods will be needed.
Hi all,
The work in question is unpublished, but extremely exciting. Dr. Campisi has developed a model for use in studies similar broadly to pioneering proof-of-concept work on the benefits of clearing senescent cells from aging tissues reported previously by James Kirkland and Jan van Deursen at Mayo Clinic, but using a system that is much more relevant to "normal" human aging.
This model is now being shared with distinguished collaborators with specialized interest in multiple diseases of aging. For instance, Julie Anderson from the Buck Institute presented thrilling results using this system in a Parkinson's disease mouse model at SENS Research Foundation's Rejuvenation Biotechnology 2014 conference. (You can get an idea of the thrust of that work here )
Importantly, however, like that earlier work, the treatment being used to ablate the senescent cells in Campisi's new system still relies on a "suicide gene therapy" approach in which a drug activates a transgenic "suicide gene" to selectively kill the cells, so it's not like there's a candidate that could actually be used in non-transgenic humans.
Michael, there are drugs and other methods of killing cells that we can borrow from the cancer research community to kill senescent cells, right? Killing cells isn't really the problem. From what I understand, the main problem in dealing with senescent cells in "normal" aging is that it's difficult to identify senescent cells and therefore difficult to selectively target them. Basically, we need a marker that a large proportion of senescent cells share. Does this research mean Dr.Campisi has solved this problem?
@Empirical - I'd guess that Dr Campisi hasn't solved the 'targeting' problem (that's pretty much what Michael has said). But if her team has recreated the Mayo clinic's work in ordinary mice (the Mayo clinic used Progeria model mice) then that is a big step forward. Progeria model mice apparently accumulate senescent cells at a much higher rate than normal mice. So you could have argued that senescent cells weren't important in aging even after the Mayo clinic's result as perhaps at normal rates of accumulation they have no effect on the mice. This is the question that the Campisi lab have probably now conclusively put to rest.
Also it was up in the air if removal of senescent cells would extend lifespan or just healthspan. The article says that the mice lived 20-25% longer than controls, although this is probably a very preliminary result and may change when the final result of the research is published.
@Empirical: as Jim suggests, the answer is basically 'no;' I'm uncomfortable explaining exactly why, but while this might help build toward an actual deliverable agent, it doesn't in a direct way give a druggable target, let alone a drug.
@Jim: Kirkwood and van Deursen's mice weren't progeria mice, if by 'progeria' you mean Hutchinson-Gilford. But like a lot of different models, they do have accelerated age-related pathology, which is often taken to make animals a model of accelerated aging ("progeria" in the loose sense) — a slippery notion that is sometimes becomes a petitio principii. (as, indeed, is the case in HGPS — see a previous discussion on Hutchinson-Gilford Progeria Syndrome (HGPS) and "accelerated aging"). The real problem with their mice was not so much that they accumulated senescent cells so fast, but that the mechanism whereby they accumulate is quite different from that encountered in 'normal' aging (as, again, is very likely the case in HGPS).
The senescent cells in these various applications of Campisi's new system acquire them either as a result of "normal" aging processes, or in established models of age-related disease in which their accelerated accumulation seems likely to parallel the "natural" course of the disease even if the basis for the model is to some degree artificial. In any case, they're all much 'cleaner' models than the horrendous mess of the animals used in previous work, and the relevance of the links they uncover between senescent cell accumulation to real degenerative aging and its pathologies — and of the effects of clearing them — are accordingly much more solid.
I'm a bit confused. The researchers at the Mayo Clinic targeted p16Ink4a-positive senescent cells in their study. Is Dr.Campisi also using this marker? If so, wouldn't the removal of these cells in a "normal" model of mouse aging and the subsequent increase of healthspan and/or lifespan indicate that p16Ink4a-positive senescent cells are a viable target?
@Empirical - Yes I was also wondering why if p16Ink4a-positive senescent cell removal has positive outcomes in mice (increased healthspan at the Mayo Clinic, 20-25% lifespan extension at the Buck Institute) why not run with this and start developing a technology to remove these cells in adult humans?
I'd guess that the mouse models used by both the Buck institute and Mayo Clinic still leave room for some doubt about whether p16Ink4a-positive cells are a good enough marker of senescent cells in 'normal' mice and humans. Don't forget that mice (even completely unmodified) are often a rubbish model of human disease or aging. Read through the archives on Fightaging and you'll see articles on Alagebrium which cleaved extra cellular matrix crosslinks in mice nicely, but when tested in humans it turned out that the crosslinks it broke in mice were only relevant in mice and weren't present/important in humans. Given limited cash for research backing the right horse is critical.
https://www.fightaging.org/archives/2006/10/age-breakers-beyond-alagebrium.php
I also am a just a layman, but read everything I can. A recent video by Dr. Arnold Caplan on the use of adipose derived MSC's is facinating:
https://www.youtube.com/watch?v=JOBrD2HxVR4
I do know Robert Lanza and the folks at OCATA have been pretty silent about their Hemangioblast Derived MSC's FDA trial on large animals at Tufts University for 10 IND's for the last year. If these cells are derived from the most primitive state, then I ask, why would these cells not be the gold standard for curing most disease.