Increased understanding and control of the immune system will be just as important to enhanced human health and longevity as advances in stem cell science. The decline of the immune system with age has many detrimental effects, some direct, some indirect. But with greater control our immune systems - even just a little more control than we presently have - many of these age-related problems can be done away with. An immune system that remains efficient and active for many more years will bring increased healthy longevity.

One measure of progress in immune system engineering is the degree to which inroads are made in repairing autoimmune diseases. This is a direct application of new knowledge, run through the existing medical regulatory system. One less subtle approach presently in the works involves destroying and recreating the entire immune system to remove the configuration issue at the root of the disease - it seems to work. A wide variety of other research and development is taking place, such as this recent example:

Hope for arthritis vaccine 'cure':

A single injection of modified cells could halt the advance of rheumatoid arthritis, [one] of a family of "autoimmune" diseases, in which the body's defence systems launch attacks on its own tissues.

...

The precise trigger for these attacks is not known, but the latest technique, so far tested only on cells in the laboratory, aims to "reset" the immune system back to its pre-disease state.

A sample of the body's white blood cells is taken and treated with a cocktail of steroids and vitamins which transforms a particular type of immune cell called a dendritic cell into a "tolerant" state. These cells are then injected back into the joint of the patient.

Professor John Isaacs, who is leading the research, said: "Based on previous laboratory research we would expect that this will specifically suppress or down regulate the auto-immune response."

Just as with stem cell science, a great breadth of work in immunological engineering produces a body of knowledge and research community that can be turned to the repair of aging in years ahead. If today researchers are attempting to repair broken immune systems, tomorrow they will be adding new immune system capabilities - such as a resistance to poor configurations brought on by aging, enhanced cancer and senescent cell destruction, or removing certain damaging biochemicals that build up with age.

The immune systems of the future will be a merging of the natural and the engineered, and will be extremely efficient and long-lasting compared to our present version. Keep an eye on present day immunological research, as it is one of the foundations of tomorrow's enhanced longevity.

How do you determine a person's age from a biomedical perspective? Not how many years they have amassed, but to what degree has the body aged relative to some median measure. This is an important question in aging research and longevity engineering - if you have no measurable metric for age, then you can't know whether or not a supposed rejuvenation medicine is working, never mind how well it is working. So a great deal of time and energy has been devoted to establishing biomarkers of aging, and you'll find some discussion on this topic back in the Fight Aging! archives:

How can you rapidly determine that you have successfully developed an anti-aging technology that works in humans if you cannot tell how advanced the aging process is in any given individual, or if you cannot even agree on a working scientific definition for aging? Obviously you can wait around to count years and deaths, but that reliable fallback is not a good approach for those of us who would like to see working healthy life extension medicine in our lifetimes.

As I mentioned back then, I think that damage repair approaches to rejuvenation science - i.e. identify and then revert biochemical changes - sidestep some of these concerns. An array of specific identified biochemical changes (such as the forms of biochemical damage listed in the Strategies for Engineered Negligible Senesence) becomes the metric for aging, and you attempt to fix or revert every change you can identify until you can prove that any specific change is benign.

In any case, we are revisiting this topic today because the most recent batch of podcasts at SAGE Crossroads discuss biomarkers of aging. Head on over and take a look.

#44 - Biomarkers of Aging - Setting the stage: What are biomarkers of aging?

a biomarker is a way to measure a parameter in a biological system or subject. All of us have in our minds how old we are. We use it as we use a clock to count the passage of time. Over a human life, we measure the passage as months, years, decades and so on, but for medical purposes, if we are going to try to develop interventions that modify the rate of aging in individuals, first we have to find a way to validate measuring aging separate from chronological age. We know that not all 50 year olds are the same. The same for all 60 years olds or 80 years olds or any other age. People vary despite their same chronological age, so we have to have measures that get at how old a person really is biologically and how to measure that, and that’s how biomarkers come in.

#45 - Biomarkers of Aging - What came out of the National Institute of Aging's biology of aging program?

it was a 10 year effort to try to find biological markers of aging that are different than chronological markers of aging. ... what we did was to create a very large colony of a variety of mice, inbred mice and inbred rats, as a source for studies looking for biomarkers of aging. ... All together of a 10 year span we had, if I remember right, 14 different laboratories involved and the biomarker research spanned the scientific spectrum from cellular and molecular model searches to whole organism behavior and sort of everything in between.

#46 - Biomarkers of Aging - Another perspective on the NIA research into the biology of aging

It’s been a very difficult process. The NIA ran a program for ten years back in the 1980s and 90s to try to identify such biomarkers and in fact was essentially not successful in that activity. The NIA invested a fair amount of money in this process, perhaps 20 million dollars, to come up with a panel of biomarkers and in the end did not come up with such and informative panel of biomarkers that could predict the chronological age of an individual within a species or the length of remaining life the individual could anticipate.

#47 - Biomarkers of Aging - What's holding the research community back?

[One stumbling block] is a lack of interest or a lack of research effort devoted to the topic. There have been major complicated human data sets where people have been tested for lots of different things, and there is some end point measure, whether they die, whether they get cancer, or whether they develop a hearing problem and so forth, and the data sets exist, but they haven’t really been evaluated by people who combine high class statistical skills and also a clear conceptual appreciation of the difference between a biomarker of aging and a risk factor for mortality.

The other stumbling block is that data sets could be improved. If this were really the major goal of the project, you would want to measure in each person or each rodent, if it’s a rodent study, a batch of different kinds of changes. Changes in kidney function, liver function, cognitive function, skin composition, and gene expression. Highly enriched data sets of that sort would have to be prepared to provide the information needed for a high level evaluation of the biomarkers of the aging rate itself.

#48 - Biomarkers of Aging - How are we going to find biomarkers of aging?

It’s gone through various times of when it was a high priority and then given a lack of success in identifying biomarkers, it lost some its priority, but I see a resurgence now given what I said in response to the previous question that we are at an important state in gerontological research where there are specific interventions that can be evaluated.

...

There is a lot of extrapolation that can be done in terms of whether our success in pre-clinical studies will translate to clinical studies, but this can only be proven by the format that is accepted in the scientific world and that’s well-controlled clinical studies. These well-controlled clinical studies can only move forward when there’s consensus on what a biomarker of aging is and how it can be applied to such clinical studies.

It is an interesting topic, wherever your views may lie.

As I've noted in the past, accumulation of senescent cells over the years is one of the root causes of age-related damage, disease, degeneration, and ultimately death:

So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

Why do senescent cells accumulate with age? It is possible that the aging immune system, suffering issues of its own, no longer destroys senescent cells efficiently enough. It is also possible that accumulation of senescent cells has a lot to do with the shortening of telomeres with age: telomeres, after all, shorten with each cell division to act as a clock that moves cells from the life cycle of division and growth into either a quiescent or senescent phase.

You'll find a couple of interesting posts over at Anti-Ageing Research summarizing the issue of senescent cells and outlining ways to approach the repair and reversal of this age-related change in our bodies:

Cellular Senescence in Anti-Ageing Research:

Since senescent cells are potentially detrimental to the tissues in which they reside, anti-ageing research has three main aims for dealing with this problem:

(1) Prevention: prevent cells from becoming senescent.
(2) Removal: remove senescent cells as they appear.
(3) Replacement: replacement of cells which have naturally or artificially been removed.

..

Therapeutic agents have the potential to specifically target senescent cells and induce programmed cell death (apoptosis). At present, no such drug is available. However, drugs that are being developed to specifically target cancer cells could one day be adapted to target senescent cells. For this to be made possible, a cell surface marker specific to all senescent cells needs to be identified. A drug can then be developed which specifically identifies that marker, binds to it and induces apoptosis.

The removal of senescent cells using therapeutic agents:

One promising area of research in the development of drug delivery systems incorporates the use of nanotechnology. Such technology has been used to create dendrimers, spheroid or globular nanostructures which are highly branched. The branched regions of these dendrimers can be used to attach molecules such as targeting and therapeutic agents. To test this nano-delivery system, [investigators] attached a targeting agent, a therapeutic agent and an imaging agent to the surface of dendrimers. The investigators chose folic acid as the tumour-targeting agent (a molecule which binds to a high-affinity receptor found on many types of tumour cells).

...

The dendrimer construct was highly toxic to [cancer cells with folic acid receptors] but had no effect on cells without the folic acid receptor. It is research like this that could one day be adapted to specifically target senescent cells.

The tools of biotechnology being developed for specific uses today - often in the cancer research community - will have very broad future applications. Nanoparticles like dendrimers are one example of many.

I thought I'd direct your attention to a generally sensible blog post I noticed recently:

As a general matter, many people are reluctant to say that a person is ethically obligated to sacrifice herself (i.e. end her life prematurely) for the sake of others. This principle may run afoul of our ethical intuitions in at least one case.

Suppose that Jeff makes several billion dollars on Silicon Valley. When asked which causes he plans on donating to, Jeff replies: "Just one. I will fund research on life extension (cryogenics, therapeutic cloning, xenotransplantation, etc.) so that I can live for as long as possible." Are Jeff's actions unacceptably selfish?

As it becomes more apparent to a wider audience that engineered healthy longevity - medicine to repair the biochemical damage of aging - is a very plausible prospect for the decades ahead, we'll see much more discussion on the topic. As that discussion broadens, I fully expect it to follow much the same lines as bioethical handwringing over past advances: a decade or so of public idiocy that is followed by an era in which people quickly forget that anybody ever claimed the advance in question was a bad idea. Look at in vitro fertilization back a ways, or the changing public discussion over stem cell science.

Sadly, I don't think much can be done about the contingent who do actually believe it is "unacceptably selfish" to invest in research that will benefit many people, one of which happens to be the investor. They are a millstone about the neck of human civilization, and an unfortunate consequence of prosperity - beneficiaries ignorant of the processes by which their comparatively great wealth is created and maintained. To be ignorant of how to create wealth is a luxury good.

But when it comes down to it, people are usually individually positive about living longer, healthier lives. Few would volunteer to die tomorrow while healthy and vigorous, and most people invest a great deal of time and energy into anticipating and defeating threats to life and limb. So I think it'll work out in the end; we just have to suffer the decade of public idiocy first, in which every dumb justification for forcing billions of people to suffer and die is trotted out and given a good airing.

As I pointed out over at the Longevity Meme this morning, some exciting news materialized over the weekend. Researchers have apparently halted an important biochemical aspect of aging in liver tissue, and have the measurements of liver function to back up that claim:

The cells of all organisms have several surveillance systems designed to find, digest and recycle damaged proteins. ... One of these surveillance systems - responsible for handling 30 percent or more of damaged cellular protein - uses molecules known as chaperones to seek out damaged proteins. After finding such a protein, the chaperone ferries it towards one of the cell's many lysosomes ... Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins. Could replenishing lost receptors in older animals maintain the efficiency of this protein-removal system throughout an animal's lifespan and, perhaps, maintain the function of the animal's cells and organs as well?

Yes, it could: the researchers demonstrated old mouse livers functioning as well as young mouse livers. On the one hand, this is solid support for a range of scientific initiatives aimed at lysosomal issues and buildup of damaging material in cells. For example, the work of the Methuselah Foundation under the LysoSENS program. On the other hand, this result suggests that - in the liver at least - the problem simply goes away if you deal with the missing receptors. This is interesting, as I was under the impression that a large portion of the issue in old humans stemmed from material that would never be broken down - the human lysosome just doesn't have the tools for the job.

This work on liver function was performed in mice; will this same sort of result hold in longer-lived mammals? We humans have tens of mouse life spans in which to build up even more impressive collections of gunk in our cells. Work on AGE-breaker drugs has demonstrated that old rodents and old humans don't necessarily have a lot in common when it comes to what sorts of biochemical gunk predominantly cause degeneration:

There are many, many different types of AGEs, and researchers have no exhaustive catalogue of them all; any given AGE-breaker is going to tackle one subset at most. Alagebrium most likely attacks a type of AGE much more common in old animals than old humans, for example - which is why it works so much better for rats than us.

Well, we shall see. I can't imagine the scientists failing to find funding to continue this line of research in one form or another.

One last item that caught my eye today was buried at the bottom of this article:

In research yet to be published, Cuervo has found that calorie restriction prevents the age-related decrease in [the chaperone system].

It's quite uncanny to see calorie restriction beneficially affect every new measure of age-related change and decline, even when that is what I'd expect based on evidence to date.

I'm a firm believer in brands and names. If you can't say a few short words in response to "what is it you work at?" and be immediately understood, then you have one more hurdle to surmount every time you're out looking for funding, deals, and partnerships. "Cancer research" is a good example. The life sciences are fantastically complex, but everyone knows where you stand with "cancer research" - those words carry a great deal of weight and shared understanding.

Unfortunately, "aging research" doesn't carry the same weight. Cancer research is well-understood to mean searching for the cure, but "aging research" has no such connotation. Something better is needed for those of us in search of a recognizable brand for engineering a cure for aging.

Back a ways, I decided to jettison use of the term "anti-aging science" as a bad deal. It carries a lot of shared understanding, but not the right sort of shared understanding - it's a gateway to communities of magical thinking and glittery cosmetics. If that was going to help serious attempts to engineer the repair of aging, the benefits to the research community would have been clear already. They are not, needless to say, and "anti-aging science" is a poisonous swamp - it is white-coated actors playing cosmetics researchers in TV commercials.

So what do you tell people you support? Once upon a time I had hopes for "healthy life extension," but I think that life extension is on the way out as a name with promise. It suffers from too much contact with the "anti-aging" community, and is at once too vague and too clinical. I'm presently in favor of "longevity science," - or "engineered healthy longevity," or the like - in absence of other good candidates. This seems to have legs, as I've seen "longevity science" used out there in other parts of the online world. It's snappy and to the point, and not yet subverted by the horrible children in the anti-aging marketplace. The only downside that springs to mind is that it does nothing to dispel the Tithonus Error - that many people think engineered longevity means being old for longer rather than young for longer.

But these are just my views. I'd be interested to see what other people think about nomenclature and branding in initiatives aimed at the repair of aging through applied science.

A large portion of the aging research community is engaged in understanding the relationship between the endocrine system and longevity. The endocrine system is an extremely complex web of biochemical interactions, feedback loops, and specialized tissues that controls metabolism and growth. It is highly influential on the longevity of a species or an individual, but understanding this system is a vast and complex undertaking. I have no doubt that researchers will still be toiling at this labor when we're well into the era of tissue engineered replacement organs and early medical nanorobots.

Some differences in life span between species can be ascribed to differences in endocrine configuration:

The complex, highly integrative endocrine system regulates all aspects of somatic maintenance and reproduction and has been widely implicated as an important determinant of longevity in short-lived traditional model organisms of aging research. Genetic or experimental manipulation of hormone profiles in mice has been proven to definitively alter longevity.

...

Here, we examine the available endocrine data associated with the vitamin D, insulin, glucocorticoid and thyroid endocrine systems of naturally long-living small mammals. Generally, long-living rodents and bats maintain tightly regulated lower basal levels of these key pleiotropic hormones than shorter lived rodents. Similarities with genetically manipulated [mammals] suggest that evolutionary well-conserved hormonal mechanisms are integrally involved in lifespan determination.

Interestingly, scientists in search of the underlying mechanisms of enhanced longevity are linking one of the first discovered longevity mutations - knockout of growth hormone receptors in mice, a large alteration to the function of the endocrine system - with changes in methionine metabolism. Methionine is one of the essential dietary amino acids, and you may recall that we have good reason to think methonine restriction plays a large role in the enhanced longevity provided by calorie restriction. We can speculate - well in advance of a good weight of evidence - that this mechanism might underlie a range of diverse longevity mutations.

Long-living growth hormone receptor knockout mice: Potential mechanisms of altered stress resistance:

Endocrine mutant mice have proven invaluable toward the quest to uncover mechanisms underlying longevity. Growth hormone (GH) and insulin-like growth factor (IGF) have been shown to be key players in physiological systems that contribute to aging processes including glucose metabolism, body composition and cellular protection.

Examination of these mutant mice across several laboratories has revealed that differences exist in both the direction and magnitude of change, differences that may result in variation in life span. Growth hormone receptor knockout mice lack a functional GH receptor, therefore GH signaling is absent. These mice have been shown to lack the heightened oxidative defense mechanisms observed in other GH mutants yet live significantly longer than wild type mice.

In this study, glutathione (GSH) and methionine (MET) metabolism was examined to determine the extent of variation in this mutant in comparison to the Ames dwarf, a mouse that exhibits delayed aging and life span extension of nearly 70%. Components of GSH and MET were altered in [growth hormone receptor knockout mice] compared to wild type controls. The results of these experiments suggest that these pathways may be partially responsible for differences observed in stress resistance and the capacity to respond to stressors, that in the long term, affect health and life span.

Look around you at the bodies of the extremely old - when was the last time you recall seeing an obese centenarian? Excess fat held over the years is a killer, and the oldest people are very rarely overweight. I noticed a paper today that works backwards from medical and mortality data to further support the same conclusion:

There has been ongoing debate about the health risks associated with increased body weight among the elderly population. One issue has not been investigated thoroughly is that body weight changes over time, as both the reasons and results of, the development of chronic diseases and functional disabilities.

Structural models have the ability to unravel the complicated simultaneous relationship between body weight, disability, and mortality along the aging process. Using longitudinal data from the Medicare Current Beneficiary Survey from 1992 to 2001, we constructed a structural model to estimate the longitudinal dynamic relationship between weight, chronic diseases, functional status, and mortality among the aging population.

A simulation of an age cohort from 65 to 100 was conducted to show the changes in weight and health outcomes among the cohorts with different baseline weight based on the parameters estimated by the model. The elderly with normal weight at age 65 experience higher life expectancy and lower disability rates than the same age cohorts in other weight categories. The interesting prediction of our model is that the average body size of an elderly cohort will converge to the normal weight range through a process of survival, senescence, and behavioral adjustment.

Become fat and stay fat, in other words, and you'll remove yourself from the picture much sooner than would otherwise be the case. In addition, your health in the years ahead will be much the worse for it. Do as you will with your life, but don't say you weren't warned.

Aschwin de Wolf continues to build up a fascinating library of work on cryonics and its history at Depressed Metabolism. The early cryonicists of the 1960s were the cultural ancestors of the transhumanist movement, and thus also of many present initiatives in other areas of the healthy life extension community. It was the transhumanist community that helped launch the Methuselah Foundation with their early generosity in donations and volunteerism, for example. One of these days I have to mock up an evolutionary diagram of branching arrows to show the creation and diversification of pro-life-extension communities from the 1950s to the present.

But back to cryonics: two new articles at Depressed Metabolism caught my eye, both looking at the early days.

A Freezing Before Bedford's

James Bedford’s freezing in January 1967 is usually regarded as the first true cryonic suspension, done immediately after legal death under controlled conditions which, though primitive by today’s standards, may have opened the possibility of eventual reanimation. Yet there was an earlier freezing that, while more problematic from the standpoint of viability, was nonetheless important in the beginning cryonics movement.

Historical Steps Toward the Scientific Conquest of Death

In December 1963 the Life Extension Society was founded in Washington, D.C., with Cooper as president, to promote the freezing idea. The September 1965 issue of the LES periodical Freeze-Wait-Reanimate carried stirring headlines: ASTOUNDING ADVANCE IN ANIMAL BRAIN FREEZING AND RECOVERY …. Dr. Isamu Suda and colleagues, at Kobe University in Japan, had detected electrical activity in a cat brain that had been frozen to -20 C ( 4 F) for more than six months and then restored to body temperature. The cat had been anesthetized and the brain removed. The blood was replaced with a protective solution of glycerol prior to freezing; the glycerol was again replaced with blood on rewarming. Not only did the brain revive and resume activity, but the brain wave pattern did not appear to differ greatly from that of a live control. Here, then, was dramatic evidence that cryonics might work, especially if possible future advances in repair techniques were taken into account.

As we continue in our endeavors to engineer the sort of future we'd like to live in, I think it behooves us to look back at past generations of advocates, activists, and entrepreneurs who had the same goal in mind. Those who ignore history are doomed to repeat its low points, and there is much to be learned from a survey of the healthy life extension communities of the past.

I missed a social interest paper from earlier this year, in which gerontologists were questioned on their views of healthy life extension and longevity science. The abstract is a fair summary of what I've seen of ongoing debates on the subject:

It is often assumed that there is broad public support for strong life extension research (i.e. research aimed at the dramatic extension of human life beyond the current maximum), and that there would be a near universal interest in using any life extending technologies that this research may produce.

In this paper we report the opinions of researchers in ageing on the controversial promise of life extension, and compare these views. This paper describes the professional attitudes, personal interest and concerns expressed by Australian and international researchers in ageing (n = 14) as expressed during semi-structured, in-depth interviews.

Researchers held varying opinions about the possibility of significantly extending human life. Some saw a limit to the extension of human life, while others did not. Some felt that research into the fundamental ageing process was a priority; others did not. Researchers tended to weigh up the potential risks and benefits of life extension with most expressing a personal interest in life extension that was contingent on the technology providing a good quality of life. Some participants were not interested in the prospect of life extension for personal reasons, because they felt the potential risks outweighed the potential benefits, or because life extension raised issues of justice and equity.

Compare this with another social science paper from earlier this year that investigates attitudes in the general populace. The results are very similar. On the one hand, it's good to see more researchers publicly expressing positive attitudes towards healthy life extension - that hasn't always been the case. But as always, those of us interested in living longer, healthier lives through science should be concerned that a good fraction of the aging research community - the people best placed to work on the fundamentals of future longevity therapies - is not all that interested in getting the job done.

"Justice and equity" in particular is a poisonous ideal when you attempt to bring it into the real world:

I find it very strange that apparently intelligent people can field this sort of argument. Replace working anti-aging medicine with, say, working heart transplants, or working kidney dialysis and see how far you get in trying to convince people that suppliers in the developed world are keeping such technologies out of the hands of others, or that we must stop using medicine that is not universally available. Quite aside from the glaring failure to understand simple economics, it is deeply depressing that we live in a world in which people argue for the enforcement of large-scale, preventable suffering and death.

Life is unfair, make no mistake. People are unequal in opportunity, capacity and the hand they were dealt at birth. To think that this truth can be removed in any way, shape or form is to betray a profound ignorance of economics and the human condition. You cannot make life better at the bottom by tearing down the top; the top is where progress happens, progress that lifts the quality of life for everyone. Punishing success in order to reward failure has predictable results - more failure and less success. The wealthy of 1950 were far worse off than the poor of today precisely because progress brings economic rewards to the successful.

The work of advocacy for longevity research is as much focused on those within the scientific community as it is on the general public. Not to convince everyone to walk in step, but to at least create a sizeable community of enthusiastic scientists - large enough to get the work done, and to sway conservative regulatory and grant organizations into ceasing their discrimination against this body of research.