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SENS Research Foundation Expands Collaboration with the Buck Institute to Work on Senescent Cells and Immune Aging

The SENS Research Foundation and the Buck Institute for Research on Aging are both based in the Bay Area, California, and collaborate on a small variety of projects relevant to the development of rejuvenation therapies. This includes clearance of the neurofibrillary tangles that appear in age-related tauopathies, to pick an example announced earlier this year. There is also some cross-pollination of researchers; the aging research field is still a comparatively small community, and people who are or have been involved in SENS rejuvenation research programs can be found scattered throughout. SENS research has been going on for long enough now to produce a fair number of alumni who have gone on to run their own labs or work in other parts of the field. Today the SENS Research Foundation announced an expansion of the Buck Institute collaboration, to include work on the intersection of cellular senescence and immune aging:

SRF and Buck Institute to Collaborate on Senescent Cells

SENS Research Foundation (SRF) has launched a new research program focused on dysfunctional white blood cells in collaboration with the Buck Institute for Research on Aging. Judith Campisi, a leading global expert on aging and age-related diseases, will be running the project in her lab at the Buck. Various types of unwanted cells accumulate during aging and affect the function of many systems, including the immune system. Some of these cells are cleared by the immune system, but some are not, possibly leading to a vicious cycle of decline. It is therefore a priority to explore techniques for eliminating these cells and rejuvenating the body, by forcing the unwanted cells to "commit suicide", and/or by augmenting the cell-killing function of healthy immune cells.

"One of our major goals is to find treatments to augment the aging immune system's defenses against senescent cells. This collaboration with SRF will enable us to explore a range of hitherto neglected ways to do that. We are extremely proud to be partnering once again with Judith Campisi's lab and the Buck on this critical project." This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors.

Aging is not a linear process; it accelerates as it progresses. As might be expected, this also appears to be more or less the case for the forms of cell and tissue damage that cause aging. When it comes to the state of health and tissues, the difference between 30 and 40 is not the same as the difference between 40 and 50 or the difference between 50 and 60. The downward pace picks up over time. This is characteristic of a self-repairing system, in that there are two primary determinants of the pace of functional decline. The first is the rate at which damage accrues, and the second is the efficiency with which that damage is repaired. The accumulation of lingering senescent cells is a good illustration of the point. Senescent cells are created constantly in our tissues, every time a somatic cell reaches the Hayflick limit on replication, or most of the time when a cell becomes damaged and potentially cancerous. Near all such cells are destroyed quite quickly, either by their own programmed cell death processes, or by the immune system. Unfortunately the immune system - just like all other agents of repair - becomes damaged with age, and its effectiveness declines. As this happens, the rate at which senescent cells accumulate increases.

Of interest in this picture is that at least some of the age-related malfunctioning of the immune system is caused by immune cells becoming senescent and lingering to cause harmful side-effects. While some researchers suggest that this might, at least at first, act as a beneficial adaptation in the face of failing resources, the same can be said of other senescent cells. They help to suppress cancer, at least at the outset when their numbers are small. But by the time they are plentiful, the harms done by their presence far outweigh any help they provide - and in the end, they produce a high degree of chronic inflammation that in fact encourages cancer development. At the present time, it is starting to look like there are multiple classes of senescent cell lingering in the body, sharing a similar set of characteristics, all harmful to health, but possibly different enough to require some tailoring of the therapies presently under development to deal with them.

Since senescent cells attack the effectiveness of the repair system set to watch over them, they encapsulate a cause of death by aging in and of themselves. Even if cellular senescence was the only form of damage that lies at the root of aging, and it is not, it would be able to kill us by crippling the immune system and then going on to produce the failure of organs and other systems as ever more cells in every tissue become senescent. Fortunately the approach of destroying these cells indiscriminately, without caring much about subtypes, seems likely to produce significant benefits based on results in mice to date. Numerous variants of this approach are presently in commercial development. Given that the first of these therapies destroy between a quarter and a half of senescent cells, and only in some tissues, the second generation yet to be developed has considerable room for improvement. That improvement will come alongside the development of better and more discriminating assays for cellular senescence, and this is likely where research into the potential varieties of cellular senescence will prove helpful.

It is also worth considering entirely unrelated efforts to restore immune function in older patients. These are likely to produce sizable benefits to health, as the failure of the immune system is one of the primary causes of frailty in the old. No-one knows whether such a restoration would sweep out a fair portion of senescent cells as well, or how this would compare with targeted therapies for destruction of senescent cells. The only real way to find out is to try it, perhaps initially through the creation and infusion of large numbers of immune cells cultured from a patient sample. Other approaches worth chasing for immune restoration in the old include regeneration of the thymus, the organ that determines the pace at which new immune cells are created, or complete destruction and recreation of the immune system in order to clear out all of the misconfigured and misbehaving cells. In the latter case, the approaches presently used to effect a cure of autoimmune disorders by clearing all immune cells are probably not safe for use in very old people, being essentially chemotherapeutics with harsh side-effects. But it should be possible to produce better methods of targeted cell killing with minimal side-effects, such as via adaptation of the programmable gene therapy approach used by Oisin Biotechnologies to attack senescent cells.

Comments

Shouldn't killing senescent cells using an old, dysfunctional immune system be less efficient than using a drug that directly kills them?

Posted by: Antonio at April 25th, 2017 12:15 AM

Based on what you stated in your blog, if I have to chose between a rejuvenated immune system and
getting rid of senescent cell, I would chose the former. It seems like I heard someone did recreate the thymus in the past year. Hopefully, there has been more progress since then.

Posted by: Robert at April 25th, 2017 1:28 AM

But are we even certain the accumulation of senescent cells is caused by a failing immune system? I seem to recall Judith Campisi saying it is the innate immune system that deals with senescent cells and that actually gets stronger with age (as a compensation for the failing adaptive immune system perhaps).

Has Judith changed her mind on this - or is the rate of senescent cell accumulation accelerating with age for other reasons (other damage - ROS etc, or perhaps just being driven by chronically activated MTOR pathway)? Or perhaps the rate of senescent cell accumulation is only going up because the small but significant fraction that are not cleared (even in youth) eventually crosses some threshold where is becomes self sustaining with the SASP creating more senescent cells than can be removed...

Posted by: Mark at April 25th, 2017 3:30 AM

Outstanding news. If we can improve the aging immune system by removing senescent cells this should feedback and improve the immune systems ability to remove other senescent cells. Bravo to SENS and the Buck and to Forever Healthy!

Posted by: Steve Hill at April 25th, 2017 6:48 AM

@Mark: All fair points, and I glossed over that part of the equation. The rate at which senescent cells are created for reasons other than replicative senesence probably increases due to the other damage of aging. Senescent cells themselves promote more senescence. I think the evidence is good for failure of the immune system to be a significant component of the overall picture, as you can lean on all of the work done on age-related failure of immunosurveillance for cancer.

Posted by: Reason at April 25th, 2017 6:58 AM

yes a number of factors are involved: Senescent cell SASP, altered intercellular communication, inflammaging and microbial burden. However I am convinced that if the immune system works better and can be rejuvenated it will help offset a number of antagonistic and integrative aging damages. The big one is Thymus rejuvenation in my view I just hope someone finds a solution to this ASAP because I think it will help reduce the impact of these secondary damages.

Posted by: Steve Hill at April 25th, 2017 7:03 AM

@Steve - I thought Thymus regeneration was already well on the way to be solved?

http://www.economist.com/news/science-and-technology/21600356-first-time-mammalian-organ-has-been-persuaded-renew-itself-engage-0

"Dr Blackburn knew from earlier experiments that FOXN1 is important for the embryonic development of the thymus, so she wondered if it might be used to rejuvenate the organ in older animals. To this end, she and her colleagues bred a special strain of mice whose FOXN1 production could be stimulated specifically in the thymus by tamoxifen, a drug more familiar as a treatment for breast cancer.

Wild mice are normally killed by predators before they are a year old, but cosseted domestic versions often make it to two or even three, so Dr Blackburn and her team did their experiments on year-old and two-year-old animals, as being roughly equivalent to middle-aged and elderly humans. In year-olds, stimulating FOXN1 production in the thymus caused it to become 2.7 times bigger within a month. In two-year-olds the increase was 2.6 times. Moreover, when the researchers studied the enlarged thymuses microscopically, and compared them with those from untreated control animals of the same ages, they found that the organs' internal structures had reverted to their youthful nature. Most important of all, they found, the density of relevant T-cells in the experimental animals' lymph was twice that of the controls."

Of course those mice were genetically engineering to upregulate FOXN1 in response to a drug. But this seems like a fairly standard gene therapy challenge no?

Posted by: Jim at April 25th, 2017 11:39 AM

@Jim yes FOXN1 is one potential way to do this. I just wish there was a concerted push to get this done because it would be very useful indeed. A recent study showed an artificial thymus too for fighting cancer lets hope there is a push for general immune decline because it could help a lot of older folks.

Posted by: Steve Hill at April 25th, 2017 4:48 PM

I think using the immune system is a great idea. Drugs won't be able to kill every cell. Look at cancer where drugs can kill 99% of the cancer cells but not all of them. That why the cancer ends up coming back. But in cancer immunotherapy can kill all of the cancer cells.

The issue is that doing it is really hard. There is still a ton is not known about the immune system and how it works. Immunotherapy has basically cured some people of certain cancers, but not others, and researchers aren't sure why. Still getting the body's immune system to clean itself out is a great path to start down, even if it will take a lot of basic research to figure out how to do it.

Posted by: Deleo at April 25th, 2017 5:11 PM

It would seem to me that if the immune system was the primary defense against sentient cell accumulation that there would be a documented subgroup of people with autoimmune conditions that experience extended life spans.

Posted by: JohnD at April 25th, 2017 7:17 PM

From the press release, it's not clear whether they will kill senescent white blood cells or whether they will "train" white blood cells to recognize and kill senescent cells in general.

Posted by: Antonio at April 29th, 2017 2:36 AM

Antonio: it's not quite either of those. The immunological clearance of senescent cells (SC) is primarily executed (pardon the pun) by natural killer cells and macrophages. One hypothesis for why SC accumulate with age is an age-related decline in the ability of these cells to clear SC. This study will probe how SC resist immune clearance, in part via different components of the SASP, to see if such factors might be changing with age (including via progressive cell-autonomous alterations of the SASP over time, or the sheer rising intensity of SASP components as the number of SC in an area rises with age), or whether age-related changes in the immune cells themselves are a more likely candidate for any declining clearance capacity.

It is, of course, also possible that we will find that there is no age-related failure, but that an unchanging but ever-incomplete clearance capacity at all ages across the lifespan allows SC to accumulate over time. In that case, the results of this work should still inform possible approaches to enhancing immunological SC clearance, by making SC more vulnerable or immune cells more effective. But it would be less straightforward, as doing so would not itself be a matter of removing some damage that causes the hypothesized age-related failure in clearance.

Posted by: Michael at April 29th, 2017 1:08 PM

Thanks, Michael! Now it's clear.

Posted by: Antonio at April 29th, 2017 1:20 PM

"Aging is not a linear process; it accelerates as it progresses. As might be expected, this also appears to be more or less the case for the forms of cell and tissue damage that cause aging. When it comes to the state of health and tissues, the difference between 30 and 40 is not the same as the difference between 40 and 50 or the difference between 50 and 60. The downward pace picks up over time."

Counterintuitively, this is quite inspiring. The sicker one gets(or older in this case(same thing, in a sense)), the faster and easier one becomes even more compromised, just as depicted in the quote above. The inspiring part is that, in theory, on the repair end of things, the reverse should work in the same manner of accelerating returns. The healthier one gets(or younger), the faster the forward progression should occur in that direction as well.

As a crude example, using both sides of that, maladaptive stress(or that beyond hormesis) has a catabolic and damaging effect on the body. First, it is simple and comes in the form of simple headaches, high blood pressure, and bad digestion. As it reaches later stages, there may be more complicated issues arising from both nervous system malfunction and damage to the body(organs, cells, etc); those issues would be seizures, vestibular chaos(dizziness, etc), cognitive decline, etc. And beyond that, once the body is further damaged and exhausted, multi-system impairment or failure, and zeroed out neuroimmunoendocrine response(making us victim to new intruders(microbial, etc) and new growths(cancer, tau, etc). Then finally is death. To go from just stressed to continuously sick, takes a bit of push and effort to overcome otherwise strong defenses, but as the barrier is breached, the dominoes start falling as momentum picks up. That said, as stress is taken off of the body(using this model in reverse) by removing microbial invaders, taking pressure off of failing organ systems(temporary dialysis, etc) and removing cancerous colonies(tumors, growths etc), the next stage forward will be reached, though like it would take some time to get past healthy defenses to make one sick, the opposite would theoretically hold true in that it would take some time to build adequate reserves to get past the invasions, growths and failures. Once the point of reserve adequacy is built, and one is back from near-death to "just" having vestibular issues, seizures, etc., it should be faster from there back to more subtle symptoms such as elevated blood pressure and cholesterol markers; and yet even faster again from there to homeostasis, or at least the original state of the person before the cascade of stress.

Ray Kurzweil has often mentioned Moore's Law when referring to both technology/singularity and radical biological life extension. He has referred to this in broad context as to moving past the knee of the curve and into a state of escape velocity. I would go out on a limb in a more isolated context in thinking the same scenario would hold true with the SENS approach. Not only will the therapies come out faster and become cheaper, but they will also be modified and become increasingly more effective. What I am not certain of, and can't exactly envision with accuracy, is whether younger patients will need lower dosages of SENS infusions due to profiles with lesser rates and ranges of damage, or whether cellular therapy will be the same for one cell and all, calling it to repair itself by removing certain obstacles and adding missing elements to prime it to function as it once was in its optimal state.

So fascinating and so much to look forward to!

Posted by: Adam at April 30th, 2017 11:55 PM

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