Through his foundation, de Grey is working to solve seven types of aging damage that he believes are the key to a breakthrough. These are tissue atrophy, cancerous cells, mitochondrial mutations, death-resistant cells, extracellular matrix stiffening, extracellular aggregates, and intracellular aggregates. It may sound like a complex salad of jargon, but de Grey claims that because science has an understanding of how to fix all these damages, aging can end for good. "It unequivocally causes far more suffering than anything else that we have to experience, and contrary to the impression that most of humanity has forced itself into, it's indeed a problem which is amenable through technological intervention."

In the future, de Grey imagines humans will develop rejuvenation clinics to regularly combat these seven issues and send people on their way. These clinics may stay in the realm of the super-rich for a short time, but de Grey believes that a movement will very quickly form to bring these technologies to the general public. "It will become impossible to get elected unless you have a manifesto commitment to have a real war on ageing. Not only in getting the therapy developed as quickly as possible, but also putting in place the infrastructure."

The goal of bringing aging under comprehensive medical control is probably humanity's oldest dream - and it is certainly humanity's foremost problem today. However, our progress toward it is lamentably slight. The history of our attempts to control aging can be summarized as a sequence of mis-steps: of misguided approaches that never had a chance of succeeding. They can each be summarized in a single word: disease, design, and deprivation. And the worst of it is that they have not even been sequential: the earlier ones have survived the arrival of the later ones.

The "aging as disease" false dawn, otherwise known as geriatric medicine, rests on the assumption that the diseases of old age are inherently amenable to the same kind of medical assault as the most prevalent diseases of youth, that is, infections. They are not. The "aging as design" false dawn emerged a century or so ago with the proposal that aging serves an evolutionary purpose. It gave rise in the early twentieth century to an approach that relies upon the idea that the genes determining the variation between species are rather few in number, and thus that it is realistic to seek to tweak those of a given species (such as Homo sapiens) so as to extend its healthy lifespan. Does the "aging as design" basis for the pursuit of medical postponement of age-related ill health actually make sense? Is it even remotely compatible with what we know about aging? Again, the painfully obvious answer is no. And yet, just as with geriatric medicine, faith in the existence of some elusive "magic bullet" has persisted in the minds of a depressing number of biologists.

By the third false dawn of "deprivation" I refer, as I hope you have guessed, to calorie restriction (CR), an intervention that was shown as early as the 1930s to extend the lives of mice and rats by as much as fifty percent. To this day, biomedical gerontology research is hugely dominated by the quest for better ways to emulate the effect of calorie restriction by genetic - or, more recently, pharmacological - means. Why is this a third false dawn? Because its true biomedical potential is, and has long been, obviously almost nil. The performance of CR itself varies inversely with the non-CR longevity of the species: longer-lived species derive much less benefit as a proportion of their lifespan, and in fact not much more benefit in absolute time. This should have been expected, since the selective pressure giving rise to the pathways that mediate the response to CR arises from the frequency of famines, which is independent of the lifespan of the organisms experiencing those famines.

But this century, step by painfully small step, things are changing. I first introduced the rejuvenation biotechnology approach to combating aging called SENS, the "Strategies for Engineered Negligible Senescence", about fifteen years ago. Since first proposed in 2002, marked progress has been made in every relevant area of research. SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging. I believe that its credibility will continue to rise as the underlying technology of regenerative medicine progresses.

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn't just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which "more research was needed", and even earlier, it was just a conjecture in some researcher's head. Hopefully, one day not too far into the future, rejuvenation biotechnologies will be normal and widespread as aspirin is today, but right now, we're in the R&D phase, so we should be patient and remind ourselves that the fact we can't rejuvenate people today doesn't mean nothing is being done or that nothing has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research - the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

A mitochondrion is a component of the cell in charge of converting food nutrients into ATP, a chemical that powers cellular function. Each mitochondrion is equipped with its own DNA. Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells they reside in, turning them into waste production facilities that increase oxidative stress - one of the driving factors of aging.

Cell nuclei are far less exposed to oxidative stress than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations. The SENS Research Foundation (SRF) team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture. As Aubrey de Grey explains, of the 13 genes SRF is focusing on, it's now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the SRF team has presented its results around the world and worked on some problems encountered in the project.

Lysosomes are digestive organelles within cells that dispose of intracellular garbage - harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste.

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT - enzyme replacement therapy - for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzyme in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics and another project relating to atherosclerosis and the clearance of 7-ketocholesterol (found in lipofuscin), which eventually spun into human.bio, an early-stage private startup. Another SRF-based approach is currently being pursued by Ichor Therapeutics, where the staff are working on an ERT treatment for age-related macular degeneration. The treatment consists of providing an enzyme capable of breaking down a type of intracellular waste known as A2E. The company earlier this year announced a series A offering to start Phase I clinical trials of its product.

As cells divide, their telomeres - the end-parts of chromosomes protecting them from damage - shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions. Normally, senescent cells destroy themselves, but some of them manage to escape destruction. The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases.

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells. This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells. SRF has funded a number of studies on the subject of cellular senescence, and it's recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focused on SASP inhibition. Further, in conjunction with Methuselah Foundation, SRF provided seed funding for Oisin Biotechnologies, a company working on a gene therapy approach to destroying senescent cells.

The extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. The component parts of this scaffolding eventually end up being improperly linked to each other through a process called glycation. The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to high blood pressure, loss of skin elasticity, and organ damage, among other problems.

In order to eliminate unwanted cross-links, the SENS approach proposes to develop molecules that sever the linkages and return tissues to their original flexibility. In order to do this, cross-link molecules need to be available to researchers attempting to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years. The lack of tools to work with glucosepane has been greatly hampering the progress of cross-link breaking research, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which supported the study financially. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price. The Spiegel Lab's scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links.

Researchers looked at the electronic medical records of 46,634 British citizens who had died at age 60 or older. The large sample size included people who were healthy as well as those who had conditions such as heart disease or dementia. They found blood pressure declines were steepest in patients with dementia, heart failure, late-in-life weight loss, and those who had high blood pressure to begin with. But long-term declines also occurred without the presence of any of these diagnoses.

Doctors have long known that in the average person, blood pressure rises from childhood to middle age. But normal blood pressure in the elderly has been less certain. Some studies have indicated that blood pressure might drop in older patients and treatment for hypertension has been hypothesized as explaining late-life lower blood pressures. But this study found blood pressure declines were also present in those without hypertension diagnoses or anti-hypertension medication prescriptions. Further, the evidence was clear that the declines were not due simply to the early deaths of people with high blood pressure.

Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) follow progressive upward trajectories from childhood to middle age, but blood pressure (BP) trends at older ages are unclear. Several studies reported flattening of the upward trend or a decrease in BP at advanced ages, although a few have reported continued BP increases. Blood pressure decreases in older age have been associated with poorer health, onset of dementia, and excess mortality. Hypothesized explanations for BP decreases in later life include (1) advancing age; (2) increasing end-of-life disease, especially heart failure, suggesting a link to the years before death rather than to age; (3) more intensive use of antihypertensive medications; or (4) that excess mortality of hypertensive individuals leaves healthy survivors with lower BP. Data to test these hypotheses are currently limited.

Observing individuals with multiple repeated BP measures over time could help clarify the causes underlying trends. If increasing end-of-life disease explains BP changes, then similar downward BP trajectories should not be observed in age- and sex-matched controls who die much later. In this study, we used the Clinical Practice Research Datalink (CPRD) to estimate clinically measured SBP and DBP trajectories for 20 years prior to death, for individuals dying at 60 years and older. Second, we compared the linear SBP trends for years 10 to 3 years before death in patients who died and age- and sex-matched controls who survived at least 9 years. These approaches aimed to separate age from end-of-life associations, and avoid healthy survivor biases.

Twenty years before death, estimated mean SBPs increased with increasing age at death (60-69 years, 139.5 mm Hg; ≥90 years, 150.0 mm Hg). All age-at-death groups initially experienced increasing SBP, reaching peak values and then declining with proximity to death. Peak SBPs occurred 14 years before death in those dying aged 60 to 69 years (mean peak SBP, 146.3 mm Hg) to 18 years before death for those dying aged at least 90 years (mean peak SBP, 150.8 mm Hg). Overall, 64.0% of individuals experienced SBP decrease of more than 10 mm Hg following the peak.

Antihypertensive medication was prescribed to 85.1% of patients for at least 1 year during the analysis period: mean SBP changed by -20.8 mm Hg from peak to year of death in those treated vs -11.2 mm Hg in those not treated. Peak SBP occurred at a mean of 15 years before death in the treated vs 14 years in those not treated. Adjustment for antihypertensive treatment made little difference to the main model results. Smoking status, alcohol consumption, and levels of physical activity measured in the 20 years prior to death had little association with SBP decreases. Weight loss (the difference between the maximum weight during the first 10 years of follow-up and weight in the final year) findings showed that patients losing at least 20 kg experienced a bigger absolute SBP decrease (mean, -24.87 mm Hg) compared with those who did not lose weight.

More work is needed to elucidate the specific mechanisms involved in late-life BP dynamics. Such studies may also be useful in addressing ways of optimizing the clinical care of older patients who experience decreasing BP. Also, downward BP trajectories before death have the potential to introduce reverse causation or "reverse epidemiology" effects in risk analyses, yielding misleading associations between BP and outcomes in older patients.

In most of our tissues, adult stem cells hang out in a quiet state - ready to be activated in case of infection or injury. In response to such injury, however, stem cells have to be able to rapidly divide, to generate daughter cells that differentiate into cells that repair the tissue. Previous research showed that TOR needs to be maintained at a low level in order to preserve stem cells in a quiet state and prevent their differentiation. But in this study, researchers discovered that TOR signaling becomes activated in many stem cell types when they are engaged in a regenerative response.

This activation is important for rapid tissue repair, but at the same time it also increases the probability that stem cells will differentiate, thus losing their stem cell status. This loss - in this case in the fly intestine, mouse muscle and mouse trachea - is particularly prevalent when the tissue is under heavy or chronic pressure to regenerate, which occurs in response to infections or other trauma to the tissue. During aging, repeated or chronic activation of TOR signaling contributes to the gradual loss of stem cells. Accordingly, by performing genetic or pharmacological interventions to limit TOR activity chronically, the researchers were able to prevent or reverse stem cell loss in tracheae and muscle of aging mice.

Mice were put on differing regimens of the mTOR inhibitor rapamycin starting at different stages of life. Rapamycin was able to rescue stem cells even when given to mice starting at 15 months of age - the human equivalent of 50 years of age. "In every case we saw a decline in the number of stem cells, and rapamycin would bring it back." Whether this recovery of tissue stem cell numbers is due to a replenishment of the stem cell pool from more differentiated cells, or due to an increase in "asymmetric" stem cell divisions that allow one stem cell to generate two new ones, remains to be answered.

The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling.

Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.

I've noticed in the last year you seem a lot more optimistic about the timeline.

I wouldn't say a LOT, but yeah, it's been a good year. Basically just the cumulative progress, both on the science and on the public attitude and funding stream. I'm still cautious, because for sure we are still really struggling for funds, but I'm hopeful.

If you were to find all the funding you'd ever need, how long until you make major breakthroughs in all 7 areas and essentially completely remove aging?

50% chance: 20 years.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?

There have been lots. On the research I would highlight our paper in Science two years ago showing how to synthesize glucosepane and our paper in Nucleic Acids Research one year ago showing simultaneous allotopic expression of two of the 13 mitochondrial genes. Both those projects have greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space. On advocacy I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative, because he is not only a successful and energetic and visionary investor, he is also a highly vocal giver of advice on this topic.

Can give your thoughts on Mark Zuckerberg's plan to "cure all diseases" within his child's lifetime? I suspect there's a lot you could talk about regarding that.

Mark is (as far as I can tell) not well-informed about this area. Unlike Page and Brin, who were quite assiduous more than a decade ago in educating themselves on matters technovisionary including medical (I first met them both in that era), Zuckerberg seems to be reluctant to reach out to those who actually know stuff. Anyone who can get me an hour of his time, you could save a lot of lives.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

The SENS strategy to migrate mitochondrial DNA (mtDNA) into the nucleus seems to be preventive engineering approach rather than a maintenance approach. In light of new techniques like killing senescent cells, why wouldn't killing off cells that have given in to mutant mitochondria make more sense?

Great question - see my early papers on the subject. Basically the issue is that the majority of mutant mtDNA in an aged body is in muscle fibres, which do not get completely taken over, only segments a millimeter or so long, so we would do much more harm than good if we zapped the whole fibre.

RepleniSENS describes the thymus rejuvenation project. How does this approach compare to directly injecting stem cells into the recipient's thymus?

Actually we have discontinued that work, mostly because we were basically overtaken. A raft of approaches seem to be working: our approach of building a new one, or growth factors to regrow the old one, or even tricks to repopulate the T cell pool by proliferation in the periphery (i.e. without a thymus).

Some researchers attempt to eliminate mutated mitochondrial genomes from the cell. Would you reckon these approaches have a chance of success?

The work you referenced is terrific, but it is intrinsically limited to mitochondriopathies that are caused by inherited, single mutations, whereas in aging we have different ones in different cells. There are some ideas out there for tipping (reversing) the selective advantage enjoyed by mutant mtDNA without being sequence-specific, but they are not all that promising yet.

Once we have an efficient senolytic drug and we can get rid of a significant number of senescent cells in the body, do we also have to clear the senescence associated secretory phenotype (SASP) that has been secreted over the years or is it something that the metabolism can naturally get rid of?

The latter. The SASP molecules have a short half-life.

Aside from funding, what do you consider to be a burden or delay for your type of research?

Nothing. Seriously, nothing at all. We have the plan and we have the people. It's all about enabling those people, giving them the resources to get on with the job.

How come the epigenetic changes and changes to our microbiome that accumulate with age are not a part of the categories of damage? When do you predict that rejuvenation approach as a solution to the problem of aging will become accepted by clear majority of scientists?

The microbiome is basically a highly dynamic population of cells, hence it is virtually certain to become right on its own when we fix everything else (even assuming that there is anything suboptimal about it in old age in the first place). For epigenetic changes, this is also the case if you mean coordinated ones that happen across all cells of a given type. If you mean drift, i.e. epimutations, my explanation for that is protagonistic pleiotropy (see my 2007 paper with that title). Rejuvenation is already accepted as a solution by most scientists, and it is being reinvented by other people. See for example the 2013 "Hallmarks of aging" paper.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?

I think we've slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that's on the order of five years away.

Given current funding, how far away from robust mouse rejuvenation do you think you are?

My estimate is 5-7 years, but that's not quite "given current funding". My overoptimism in saying "10 years" 13 years ago consisted entirely of overoptimism about funding - the science itself has not thrown up any nasty surprises whatsoever - but nonetheless I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinouts from the SENS Research Foundation) and investors, so it's not only philanthropy any more. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that's for sure, but I'm feeling a lot surer that the funding drought's days are numbered than I felt even two or three years ago.

It was some time ago that you guys published your paper on inserting the enzyme into white blood cells to help them break down 7-ketocholesterol, I know a company was spun out not to long after that. Are they making good progress?

Actually, of all our (so far five) spinouts, that's the one that has rather lost its way. We are working to reboot that work and get it moving more promisingly. A lot of the problem was that it was bankrolled by one wealthy person, so that (rather like Calico) it had no incentive to let the world (or even me) know what it was doing.

When would you guess that we will have the first, direct evidence of human rejuvenation through removal of senescent cells (also considering self-experimenting individuals, which could get there first)?

To start at the end: if it works, the first evidence will indeed quite probably be from self-experimentation. Of course it will be n=1 so it will be very provisional evidence, but you knew that. So, when? - that mostly depend on the extent to which humans reproduce what has been seen in rodents, where the benefits of removing senescent cells were a lot broader than I (or anyone, I think) would have anticipated. We just don't know.

You have recently accepted a position as Vice-President of New Technology Discovery at BioTime Subsidiary AgeX Therapeutics. Can you give an overview of why you accepted this position and how it affects your current work at SENS?

I'm still defining my role there, but it is a big deal. I am there 30% so my primary affiliation remains SENS Research Foundation. But the emergence of the private-sector component of the rejuvenation biotech effort is a hugely important recent advance, and for me to have an official foot in both camps makes a strong statement. Also, it is a huge thing for me to be finally working closely with Mike West, who has been a hero of mine for 20 years. The two roles will certainly dovetail a lot: at AgeX my basic task is to come up with new therapeutic ideas, and naturally that will feed off what we are doing and have done at SRF.

Given that cells can reverse their age through induced pluripotency, do you see this as a viable strategy for reversing aging in humans, or is it too difficult and dangerous to do in vivo?

As of now it's definitely dangerous in terms of its carcinogenicity. However, we may be able to reduce that soon. I am particularly excited by the recent work of the awesome researcher Vera Gorbunova on the difficulty of dedifferentiating cells from naked mole rats; I suspect that that work may uncover ways to be more selective and controlled with in vivo dedifferentiation.

Has your position on the relative importance of the stem cell side of aging changed over the years? I know that in earlier years I was somewhat convinced that stem cell decline was fairly secondary to other parts of SENS.

It very much remains to be seen. In some tissues, like the substantia nigra where cell loss causes Parkinson's disease, I'm pretty sure we will indeed need stem cell therapy. In other places, the failure of stem cells to maintain their numbers and/or their proliferative vigour seems to be quite largely determined by the systemic environment, i.e. by what is and is not present in the circulation, and there I agree that recovery is quite likely to be largely spontaneous once we fix other stuff.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?

We don't, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Medicine and BioAge respectively). They are both awesome and massively committed crusaders for this mission. Check out the BioData West conference that will occur in San Francisco a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

With the recent departure of Calico's Head of R&D for GSK, do you think that there is a chance that Calico might now redirect its efforts in a more productive direction?

No. A good approximation to how Calico operates is as two entities: one that is essentially Genentech 2.0, setting itself up to make massive money from big deals with other traditional pharma, and one that is to pursue its actual remit, namely to defeat aging. Barron was squarely on the former side. The latter side is led by David Botstein, who is as pure a basic scientist as they come and has no time whatsoever for "dreamers" who think we might actually know enough already to be able to develop therapies. His philosophy is unfortunately permanent: no amount of progress will make him become translational and cease to be 100% discovery-focused. I don't remotely blame him - he is who he is. I only slightly blame Levinson: there was nothing wrong with hiring a chief science officer to do discovery, the only thing he got wrong was not also to hire a chief technology officer (me, obviously) alongside him. The people who have all the blame are Larry and Sergey, for allowing their billions to be wasted like this and not having the guts to step in and impose a change of direction.

Given that it's such an emotionally charged field how do you personally, and SENS in general, remain objective and keep hope from interfering with your work?

That's not so hard as you might think. Ultimately, we are driven by the desire to increase the chance of success, or equivalently to reduce the likely time until success - but from what to what is secondary. If we hasten the defeat of aging by a year, who cares whether it's from 2050 to 2049 or from 2030 to 2029? - it's still 40 million lives.

You have been wrong in the past with your expectation of peoples willingness to get onto this idea. Thus I can easily see a path where this technology is proven enough to be clearly happening but most people just don't care and the funding is still very hard to come by. Have you given much thought to this potential scenario?

You're right that I was overoptimistic in the past about the willingness of other high net worth individuals to follow in the wake of Peter Thiel, who started funding us in 2006. However, when it comes to support from scientists, I have never made such a mistake - I always knew it would take robust mouse rejuvenation. I have the advantage in that regard that the community in question is just the most credentialed, authoritative biogerontologists - no one else. Thus, they are (a) really few in number (truly, we are talking about something like a dozen people), (b) scientists (hence I know how they think, unlike billionaires) and (c) people I know well, personally. So I have very strong confidence regarding what determines what they say publicly.

Many wealthy celebrities and smart individuals can easily afford to invest into SENS. How come they are not?

Everyone has rationalisations. The key thing to remember is that humanity has been hoping against hope for a cure for aging since the dawn of civilisation, and it has been suckered time and time again into believing we had one, so there is a rather strong incentive not to get hopes up. And if something is impossible, its desirability is irrelevant: there is still no basis for funding it. So it falls to the small minority of wealthy people who are also truly independent-minded to support this work. Yes, people like Elon Musk may well feel rather ashamed a decade or two from now that they didn't do more earlier. But we're working on it.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?

Massively! A huge thing that I say all the time is that advocacy is one thing that absolutely relies upon diversity of messenger. Different people listen to different forms of words, different styles of messaging, etc. The more the better.

Is there an accepted causal or ultimate theory of aging? There are hypotheses and different schools of thought. It's not so mature that there's total consensus. There are relatively few exciting fields of biology where there's total consensus. In aging, there's a school of thought that it's all about damage and you have to repair that damage. There's another school it's all about regulation and epigenetics, and if you get the cell in the right epigenetic state then it can repair its own damage; a young cell is much more powerful at repair than an old cell.

Then there's hallmarks of aging - about nine components - and maybe you have to get all of them pushed back for rejuvenation. I like this version where they talk about specific biological mechanisms. If you fight or leverage those mechanisms you get your best shot at treating aging. Why we age is less useful than the mechanisms, but having some intuition for why the mechanisms are the way they are can help you manipulate them. And very often you want to manipulate them in an unnatural way, and that requires a deeper understanding. If you're trying to do something totally natural your protocol is clear. If you find that in the western world we're eating a lot of marbled cow that didn't exist in the ancient days, all you have to do is get rid of the marbled cow and you're all set. On the other hand if you're trying to get people to live past 150, there's no precedent for that.

Certainly if you could fix all nine hallmarks at once that would do well to solve aging. Reversal of aging has been demonstrated in simple animals. Some people will dismiss those as too simple - because they have such a short life already, it's not surprising you can make them live longer. But I think it's quite clear that aging is programmed in some sense. It's not like you've been programmed to die at some age, but the laziness of evolution has resulted in your program to not avoid dying. Over evolutionary time, to use analogy, it was not cost effective to invest a lot of your precious food to live longer because you're going to get eaten by a wolf anyway.

To address the hallmarks of aging, the idea is to take the subset of genes that has been demonstrated to work for longevity or aging reversal in smaller organisms and reconfigure them into something that's usable in gene therapy. You change it from longevity that requires introducing it into the germ line, which is not really a good strategy for humans because most of us that want longevity are already past the zygote stage, and we're reconfiguring it as a adeno-associated virus gene therapy.

How far off is age reversal? The simple answer is, I don't know. Probably we'll see the first dog trials in the next year or two. If that works, human trials are another two years away, and eight years before they're done. Once you get a few going and succeeding it's a positive feedback loop. The FDA doesn't need to classify aging as a disease in order to treat it. If you actually have something that causes aging reversal, they'll approve it. You'll frame it in conventional terms, but it can have additional benefits. In other words If you have something that fixes one disease problem and happens to fix a bunch of others, you don't need to put them all on the label. The FDA doesn't stop you for using things off label or curing two things at once.

Two companies say they'll continue offering DNA-altering materials to the public. The companies, The Odin and Ascendance Biomedical, both recently posted videos online of people self-administering DNA molecules their labs had produced. Following wide distribution of the videos, the FDA last week issued a harshly worded statement cautioning consumers against DIY gene-therapy kits and calling their sale illegal. A growing number of cases of DIY gene therapy are putting the health regulator in a difficult situation as individuals argue that no law stops them from self-administering the substances. In fact, there is a long history of scientists carrying out experiments on themselves, including some Nobel Prize winners. Last month, Josiah Zayner, CEO of The Odin, which sells DIY biology kits and supplies through its website, posted a video in which he injected himself with the gene-editing tool CRISPR during a biohacker conference.

The problem facing regulators is that interest in biohacking is spreading, and it's increasingly easy for anyone to obtain DNA over the internet. It's also easy to get hold of the recipes necessary to carry out gene editing using CRISPR, a potent new technique for modifying DNA. In October, Zayner's website began selling low-cost copies of a DNA molecule containing the necessary genetic information to deactivate the human gene for a certain protein, myostatin, using CRISPR. Human DNA can be purchased through a number of other companies that cater to research labs. The difference is The Odin markets its DNA to amateur biologists. The materials sold by The Odin also can't be directly used to alter a person's genes. Instead, they contain DNA that would have to be produced in larger amounts, purified, and then delivered to the body using methods well beyond the skills of most consumers.

At least one other company appears to have begun offering finished gene-therapy preparations directly to patients for their own use. In October, an HIV patient was filmed injecting himself with a gene therapy designed to generate antibodies that he believed would help his body destroy cells infected with the virus. The material he used was supplied by Ascendance Biomedical, an until recently unknown startup company that promotes "decentralized" testing of new drugs. The company is also developing a herpes vaccine, as well as a follistatin gene therapy to boost muscle mass and reduce fat. Aaron Traywick, the CEO of Ascendance, says Ascendance plans to make both of those therapies available for self-administration by early next year.

The harmful effects of being overweight have been underestimated, according to a new study. Previous studies have suggested that the optimum body mass index (BMI), at which the risk of death is minimised, appears to be above the range normally recommended by doctors, leading to claims it is good for health to be mildly overweight. However, scientists suspect these studies do not reflect the true effect of BMI on health, because early stages of illness, health-damaging behaviours, such as cigarette smoking, and other factors can lead to both lower BMI and increased risk of death. This makes it difficult to estimate how BMI actually influences risk of death (the causal effect), as opposed to the observed association between BMI and risk of death. This aim of this study was to assess the causal link between BMI and risk of death.

Using HUNT, a Norwegian population-based health cohort study based in a rural county with 130,000 residents, researchers were able to see how mortality in the parents related to both their own BMI (the conventional approach) and to the BMI of their adult children. Because BMI of parents and their offspring is related, due to genetic factors, offspring BMI is an indicator of the BMI of the parents. The BMI of adult children is not influenced by illness among the parents, therefore using offspring BMI avoids the problems inherent in simply relating the BMI of the parents to their risk of death.

The health records of around 30,000 mother and child pairs and 30,000 father and child pairs were assessed to examine the extent to which BMI may influence mortality risk in a situation that is not biased by "reverse causation" - illness leading to low BMI rather than BMI influencing illness. The team found that when offspring BMI was used instead of the parent's own BMI, the apparent harmful effects of low BMI were reduced and the harmful effects of high BMI were greater than those found in the conventional analyses. Importantly, the results suggest that previous studies have underestimated the harmful effects of being overweight. The current advice from doctors to maintain a BMI of between 18.5 and 25 is supported by this study, and the widely reported suggestion that being overweight may be healthy is shown to be incorrect.

Memory loss is a common characteristic of normal aging, and is greatly accelerated in some neurodegenerative diseases. The causes of memory loss during normal aging are not completely understood. Atrophy of some brain areas has been shown in normal aging and changes in intrinsic neural electrical excitability associated with oxidative stress have been hypothesized as potential causes. Subtle perturbations in stabilization of neuronal cytoskeleton, reminiscent of those occurring during Alzheimer's disease (AD) neurodegeneration, may also be an important underlying cause of age-associated neuronal dysfunction and cognitive decline. In this line, modifications of tau expression and status akin to those of tauopathies are also typical of normal aging and their distribution pattern correlates with memory capabilities.

In the search for predictive blood biomarkers of AD cognitive decline, some studies have found that mid-regional proadrenomedullin is elevated in the plasma of AD patients and that the concentration of this peptide could have predictive value in the progression from predementia to clinical AD, although a recent study found no correlation. The proadrenomedullin gene, adm, generates two biologically active peptides: proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM).

Expression of these peptides is widespread and several functions have been ascribed to them, including vasodilatation, bronchodilatation, angiogenesis, hormone secretion regulation, growth modulation and antimicrobial activities, among others. In the central nervous system (CNS), AM is expressed throughout the whole brain and spinal cord where it acts as a neuromodulator. It has been shown that plasma levels of AM increase with normal aging.

Knockout studies have shown that total abrogation of adm results in embryo lethality. To circumvent this problem, we generated a conditional knockout model where adm was eliminated just from neurons. Consequently, we have shown that aged mice that lack neuronal AM have better contextual and recognition memory than their wild type littermates. In parallel, the brain cortex and hippocampus of these mice have a lower accumulation of phosphorylated tau, suggesting that tau may be the link between lack of AM and memory preservation, although we cannot rule out other alternative molecular pathways. In addition, we also showed that older human individuals present higher levels of AM and lower levels of acetylated tubulin in their brains than younger controls.

Our data suggest that reducing AM/PAMP levels may constitute a novel path to preventing or delaying memory loss. A few years ago, a particular single nucleotide polymorphism (SNP) close to the adm gene was found to be responsible for a natural reduction in the circulating levels of AM and to correlate with cancer susceptibility. Therefore, it would be interesting to test whether carriers of this SNP are more protected from developing memory impairment. Also, several physiological inhibitors of AM have been proposed for clinical development, and some of these inhibitors may be used for the pharmacological prevention of age-related memory loss.

Researchers report creating a biologically accurate mass-production platform that overcomes major barriers to bioengineering human liver tissues suitable for therapeutic transplant into people. The new process allows researchers to bioengineer single batches of up to 20,000 genetically matched, three-dimensional and highly functional liver micro-buds. When combined, the batch has a sufficient quantity of liver cells and size feasibility for transplant into a person with liver failure, or for drug testing. The liver tissues were also generated entirely from human induced pluripotent stem cells (iPSCs), making the process free of animal feeder byproducts used to make cells for research purposes - a barrier to the cells being used therapeutically.

"Because we can now overcome these obstacles to generate highly functional, three-dimensional liver buds, our production process comes very close to complying with clinical-grade standards. The ability to do this will eventually allow us to help many people with final-stage liver disease." The researchers stress continued research and refinement of their process is required before initial clinical trials could begin, and estimate this might occur in the next two to five years.

Over the past five years the reseearch published several studies that made continuous progress into defining the precise genetic and molecular blueprints needed to mimic natural human development. This allows the researchers to develop and bioengineer functional, three-dimensional human mini livers in the laboratory. To help overcome the biological challenge of animal-product feeder cells in the current study, the team used their fine-tuned formula of genetic and molecular components to generate the liver tissues in custom-designed, U-shaped bottom micro-well cell plates. The plates use a combination of chemistry techniques to form a finely structured film inside the micro-wells, designed to nurture the developing liver buds.

But prior to this step, the researchers started mass production by initially using the donor-derived iPSCs to grow three critical types of liver progenitor cells needed to generate healthy livers. These include hepatic endoderm cells and both endothelial and septum mesenchyme cells. Study data show this generates robust and highly functional progenitor cells that are placed into the custom-designed, film-coated micro-wells. The progenitor cells then engage in high levels of molecular cross-communication to form into self-organizing, three-dimensional liver buds.

Sarcopenia is defined as age-related loss of skeletal muscle mass and strength, a condition that worsens subjects' quality of life. Clarification of molecular mechanisms underlying sarcopenia development is important to devise effective approaches to treat this condition. Several lines of evidence support the idea that in skeletal muscle chronic inflammation and reactive oxygen species (ROS) accumulation due to redox imbalance contribute to sarcopenia development, and chronic inflammation in aging skeletal muscle is positively correlated with sarcopenia development in humans and mice.

The pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) both decrease skeletal muscle mass by causing inflammation and subsequently facilitating muscle proteolysis, ROS accumulation, and growth hormone resistance. Moreover, excess ROS accumulation causes oxidative damage to skeletal muscles, resulting in myofibers loss. Both inflammation and ROS accumulation inactivate "satellite cells", the precursors of skeletal muscle cells, thereby accelerating sarcopenia development.

Previous studies reveal that expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiological stimuli, such as hypoxia and pressure-overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a senescence-associated secretory phenotype (SASP) factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathological states and contributes to development of aging-associated diseases.

Although ANGPTL2 hyperactivation is associated with age-related diseases, ANGPTL2 function in sarcopenia development remains unknown. Here, we investigated the roles of ANGPTL2 in sarcopenia development using aging mice. We report that ANGPTL2 expression increases in skeletal myocytes of aging mice and that running exercise decreases that expression, suggesting that excess ANGPTL2 signaling in aged skeletal muscular myofibers accelerates sarcopenia development. Moreover, ANGPTL2 deficient mice showed attenuated loss of skeletal muscle by reduced muscular inflammation and ROS accumulation and increased satellite cell activity. To the best of our knowledge, this is the first report showing that ANGPTL2 signaling may accelerate sarcopenia pathologies.

Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called beta-amyloid inside neurons. Most treatments focus on reducing the formation of amyloid plaques, but these approaches have been inconclusive. As a result, scientists are now searching for alternative treatment strategies, one of which is to consider Alzheimer's as a metabolic disease.

Researchers looked at mitochondria, which are the energy-producing powerhouses of cells, and thus central in metabolism. Using worms and mice as models, they discovered that boosting mitochondria defenses against a particular form of protein stress, enables them to not only protect themselves, but to also reduce the formation of amyloid plaques. During normal aging and age-associated diseases such as Alzheimer's, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. Since mitochondria provide energy to brain cells, leaving them unprotected in Alzheimer's disease favors brain damage, giving rise to symptoms like memory loss over the years.

The scientists identified two mechanisms that control the quality of mitochondria: First, the "mitochondrial unfolded protein response" (UPRmt), which protects mitochondria from stress stimuli. Second, mitophagy, a process that recycles defective mitochondria. Both these mechanisms are the key to delaying or preventing excessive mitochondrial damage during disease. "These defense and recycle pathways of the mitochondria are essential in organisms, from the worm C. elegans all the way to humans. So we decided to pharmacologically activate them." The team started by testing well-established compounds that can turn on the UPRmt and mitophagy defense systems in a worm model (C. elegans) of Alzheimer's disease. The health, performance and lifespan of worms exposed to the drugs increased remarkably compared with untreated worms. Plaque formation was also significantly reduced in the treated animals.

Most significantly, the scientists observed similar improvements when they turned on the same mitochondrial defense pathways in cultured human neuronal cells, using the same drugs. The encouraging results led the researchers to test in a mouse model of Alzheimer's disease. Just like C. elegans, the mice saw a significant improvement of mitochondrial function and a reduction in the number of amyloid plaques. But most importantly, the scientists observed a striking normalization of the cognitive function in the mice.

The mechanistic target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses. The name TOR (target of rapamycin) is derived from its inhibitor rapamycin. We now know that the role of mTOR goes far beyond proliferation and coordinates a cell-tailored metabolic program to control cell growth and many biological processes including aging, cellular senescence, and lifespan.

Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. Rapamycin was shown to extend the lifespan of genetically heterogeneous mice at three independent test locations by about 10-18% depending on sex. Interestingly, treatment was only started late when the mice were 600 days of age equivalent to roughly 60 years of age in a human person. This proposes that inhibition of mTOR in the elderly might be enough to prolong life. The findings were confirmed and extended in mice, in which rapamycin treatment started earlier. However, they failed to substantially observe larger effects on longevity.

It is now accepted that mTOR inhibition increases lifespan; yet, the mechanism through which this occurs is still uncertain. mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. However, many researchers directly link the longevity effects of mTOR inhibitors to a decrease in aging. Conserved hallmarks of aging have recently been proposed and include telomere attrition, epigenetic alterations, genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.

Cellular senescence has been suggested to function as a tumor suppressor mechanism and promotor of tissue remodeling after wounding. However, senescent cells may also directly contribute to aging. Senescent cells show marked changes in morphology including an enlarged size, irregular cell shape, prominent and sometimes multiple nuclei, accumulation of mitochondrial and lysosomal mass, increased granularity and highly prominent stress fibers that are accompanied by shifts in metabolism and a failure of autophagy. Interestingly, many of these phenotypes are regulated by mTORC1 in various cell types. The secretion of proinflammatory mediators by senescent cells contributes to aging and has been termed senescence-associated secretory phenotype (SASP). Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A.

Despite maintaining a nondividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence often show a shift to glycolytic metabolism away from oxidative phosphorylation (which is also observed in proliferative cells), despite a marked increase in mitochondrial mass and markers of mitochondrial activity. This might stem from a rise in lysosomal pH as a consequence of proton pump failure, which leads to an inability to get rid of damaged organelles such as mitochondria caused by a failure of autophagy. Dysfunctional mitochondria not cleared by autophagy in senescent cells produce reactive oxygen species, which cause cellular damage including DNA damage. mTORC1 has been postulated as main driver of these metabolic changes. Hence, rapamycin treatment prevents metabolic stress and delays cellular senescence.

We are a development stage company with intellectual property rights to novel therapeutic antibodies and chemically activated vaccines in all major markets. These rights have been developed from discoveries indicating the power of the immune system to use covalent bonding as the basis for synthesizing antibodies that neutralize and remove target antigens with efficacy and safety superior to conventional antibodies.

The two classes of therapeutic monoclonal antibodies (MAbs) being developed by Covalent, Inc are: (a) irreversible MAbs (iMAbs), which bind and neutralize the target antigen with virtually infinite affinity, (b) catalytic MAbs (cMAbs), which hydrolyze and destroy the target antigen in an enzyme-like manner. Covalent, Inc has proof-of-principle for superior efficacy and diminished side effects of the cMAbs/iMAbs compared to conventional MAbs that bind the target antigen reversibly. Covalent's cMAbs/iMAbs are isolated from the innate immune repertoire that has developed by Darwinian evolution, and immunization with Covalent's electrophilic antigen analogs induces the synthesis of the cMAbs/iMabs adaptively.

Covalent is in a position to generate cMAbs/iMAbs to diverse antigen targets for development as immunotherapies. In addition, Covalent is developing the electrophilic antigen analogs as therapeutic and prophylactic vaccine for unmet medical needs. Covalent has in hand: (a) candidate immunotherapeutic cMAbs to amyloid proteins for treating central nervous system and systemic amyloidosis, and (b) a candidate electrophilic vaccine for treating and preventing HIV infection.

Mesenchymal stem cells (MSCs) are pluripotent cells that play crucial roles in tissue maintenance, repair, and regeneration. However, data suggest that beneficial functions of MSCs may become compromised with age; this is closely associated with age-related loss of repair and regenerative capacity of different tissues. Bone marrow-derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging.

Autophagy is a process in which cellular components such as proteins and damaged mitochondria are engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled in order to maintain cellular homeostasis. Autophagy has been widely studied as a mechanism for anti-aging effects and in alleviating age-related diseases. Recent studies have indicated that autophagy is required for maintaining the stemness and differentiation capacity of stem cells. It has been reported that autophagy is a crucial mechanism in the maintenance of the young state of satellite cells, and failure of autophagy causes declines in the number and function of satellite cells. Autophagy can protect BMMSCs from oxidative stress, which indicates that autophagy plays a protective role in cell aging. Conversely, autophagy also has been proven to be a requirement for maintenance of replicative senescence of MSCs. Therefore, whether and how autophagy regulates MSC aging remains unclear.

Bone marrow-derived mesenchymal stem cells have been regarded as the main source of osteoblasts for skeletal repair. It has been reported that degenerative changes of BMMSCs in humans and rodents during aging are associated with bone aging. Bone marrow-derived mesenchymal stem cells tend to partially lose their self-renewal capacity and differentiate into adipocytes instead of osteocytes with aging, which causes bone loss and fat accumulation. Our findings showed that aged BMMSCs had decreased osteogenesis, elevated adipogenesis and decreased proliferation compared with young BMMSCs; these results are in line with the previous findings.

We speculate that decreased autophagy in aged BMMSCs might be one of the causes of degenerative changes of aged BMMSCs, and bone loss by decreased autophagy could be a potential new mechanism of bone aging. The results of the manipulation of autophagy in both young BMMSCs and aged BMMSCs confirmed our speculations. As an autophagy inhibitor, 3-MA was used on young BMMSCs; the results showed that inhibition of autophagy not only reduced osteogenesis and promoted adipogenesis but also inhibited proliferation of young BMMSCs, which indicated that decreased autophagy could turn young cells into an aged state with degenerative properties. Meanwhile, the autophagy inducer rapamycin could partially convert aged BMMSCs to a young state by increasing osteogenesis, reducing adipogenesis and promoting proliferation. In summary, we conclude that activation of autophagy can restore degenerative properties of aged BMMSCs via regulating oxidative stress and p53 expression.