BH: [The Strategies for Engineered Negligible Senescence, or SENS] describes a whole battery of medical treatments that could theoretically defeat the aging process. These treatments range from relatively simple ones like injecting people with enzymes that can break down tough wastes inside of cells, to highly advanced ones like genetically altering trillions of somatic cells in full grown adults. Considering the differential technical challenges, what SENS therapies will most likely become available first, and which will be developed last?

AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn't like to make the call, because the hardest ones are the ones that the Methuselah Foundation and I are prioritising in terms of the early research. In other words, we're hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce.

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BH: At one point in your book, you criticize the Food and Drug Administration’s (FDA) drawn-out medical approval process and suggest that drugs should instead be approved after completion of Phase 2 trials. Why do you want such a change, and won’t it lead to more deaths thanks to unsafe drugs and medical procedures becoming available?

AdG: I want this change because it will save more lives than it costs. This question has been carefully analysed by experts and it’s clear that we are vastly over-cautious now in approving drugs. That over-caution is not the fault of the FDA or the government, because it reflects public attitudes: every death from an unsafe medical treatment causes an outcry and a lot of legal action, whereas we turn a blind eye to death from the unavailability of good drugs. But when aging is recognised as defeatable, public opinion will become more rational in this regard, and so will public policy.

It's a long piece - there's much more to read though, so head on over and do just that.

Personally, I'm not fond of bioethics as a field - its members all too often serve as no more than useful mouthpieces for those who work to suppress freedom of research and development. There will always be demagogues and popular opinion-mongers, but that arena would much more constructive in the absence of empowered bureaucrats and political appointees who delight in shackling a ball and chain to progress. As things stand, modern bioethics all has the air of supplicants to majesties, of begging for scraps and the simple freedom to make progress.

If unelected, unaccountable, uncaring government employees didn't have the power to control the future of your access to medical technology, you could cheerfully ignore bioethicists as another bunch of crazies - men and women busy overthinking the issue of common sense - if you so decided. The world would be a better place for that freedom.

In any case, take a look at this piece that references the Longevity Dividend Initiative:

Given that many people see longevity science itself as unethical, it is not surprising that proposals to invest greater funding into tackling aging, rather than research on specific diseases, will likely be met with strong opposition and protests that this is unfair. For the latter proposal implicates the allocation of scarce resources, and thus it raises complex questions of distributive justice. Is it fair, the critic will ask, to divert resources dedicated to saving lives (e.g. with possible treatments for cancer, AD, etc.) to medical research that seeks to merely extend lives? Let us call this the Fairness Objection to prioritizing aging research.

In this paper I will examine, and critique, this Fairness Objection to making aging research a greater priority than it currently is. The Fairness Objection presumes that support for the Longevity Dividend is limited to a simplistic utilitarian justification. Utilitarians invoke a mode of justification that is, at base, aggregative. Thus the critics of utilitarianism charge that it is a moral theory that maintains that imposing high costs on a few could be justified by the fact that this confers benefits on others, no matter how small these benefits may be as long as the recipients are sufficiently numerous.

On the other hand, given that the course of one's life is a private matter, how about we all just get on with supporting, advocating, fundraising, and conducting longevity research as we see fit? Unfortunately, that delightful thing called government allows naysayers to grab the reins of power and interfere in every private endeavor. Plurity of choice is crushed beneath the battle over control. It is a despicable state of affairs, and I don't see how playing within the system - according any legitimacy to those who would use force to remake your every private choice - will make things better in the long term.

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.

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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 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.

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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.

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.

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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).

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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.