Aging researchers Leonid Gavrilov and Natalia S. Gavrilova have posted a draft on genetics and aging to Longevity Science. Recall that these two are behind the reliability theory of aging; I find their perspectives are usually quite different to those at the biogerontological end of the research community. If I had to sum it up in a few words, these researchers work somewhere toward the more analytical end of the triangle formed by systems theory, biogerontology and actuarial studies. Differing perspectives are hard to create and their collision is often the source of new insight - therefore they are valuable.

In molecular genetic studies of human aging traits, the gene association studies remain the most common research approach. In these studies the effect of candidate genes on longevity is analyzed by comparing gene frequencies between affected individuals (cases) and unaffected control individuals. Comparison of candidate gene frequencies among centenarians and younger controls is a typical example of such studies. Another molecular genetics approach - the genome-wide linkage scan of genes, is a relatively new direction of research. Linkage analysis is a mapping of genetic loci using observations of related individuals (pairs of affected and nonaffected siblings, for example). This direction of research has a potential for obtaining interesting results, although the success of genome-wide scans of complex human diseases requires large sample sizes, considerable effort and expense.

...

A review of gene-longevity association studies revealed that different studies often produced inconsistent and even contradictory results.

...

Most chronic diseases in later life are complex multifactorial disorders. Multifactorial disorders are influenced by multiple genes, often coupled with the effects of environmental factors. Many diseases common to old age, such as late-onset Alzheimer's disease, heart disease, diabetes are now considered to be multifactorial disorders. Most genes associated with multifactorial disorders have low penetrance, which means that the likelihood of developing disease among genotype carriers is low. Thus, the individuals with disease-related genes do not necessarily succumb to disease. With favorable lifestyle and environment there is an opportunity for individual with genetic risk factor to delay and even to avoid the disease.

All of which suggests we should be realistic when it comes to the likelihood of finding any simple correlations within the fantastically complex system formed by a lifetime of interaction between genes, the machinery that carries out their programming, and the world within which the resulting humans operate.

Not to harp on the same point over and over, but this helps to demonstrate why it is imperative we do all we can to intelligently reduce the complexity of our attempts to extend the healthy human life span. Categorizing changes in our biochemistry with age and developing the means to revert or repair those changes is a good deal less complex than either (a) gaining a complete understanding of human biochemistry or (b) attempting to change that biochemistry to produce the damage of age more slowly.

To put it more clearly, why does it matter exactly how it is our metabolism develops broken mitochondrial DNA with age if we have identified that change as pivotal and important, and know how to develop the means to repair it? Let's repair it first, then worry about the rest of the picture. It's important to get the priorities straight.

People built good, workable bridges long before the development of mathematical and engineering tools required to formally determine the best bridge-building strategy in any given case. Engineering our way to a cure for aging is no different in essence: good results are possible in the absence of complete understanding of the system, and by constraining the complexity of the work, it becomes much more plausible to see significant progress in our lifetimes.

You might recall that different fatty acid or lipid composition in cell membranes was floated as a reason for the ninefold longevity of naked mole-rats over related rodent species. Plenty of oxidative stress in the older mole-rats, but little sign of biochemical damage resulting from it - in comparison to those other rodents long since aged to death, that is. Better, more damage-resistant building blocks down at the molecular level might be the cause:

Underlying causes of species differences in maximum life span (MLS) are unknown, although differential vulnerability of membrane phospholipids to peroxidation is implicated. ... membranes of longer-living, larger mammals have less polyunsaturated fatty acid (PUFA). ... Both species had similar amounts of membrane total unsaturated fatty acids; however, mice had 9 times more docosahexaenoic acid (DHA). Because this n-3PUFA is most susceptible to lipid peroxidation, mole-rat membranes are substantially more resistant to oxidative stress than are mice membranes ... suggesting that membrane phospholipid composition is an important determinant of longevity.

A forthcoming Rejuvenation Research paper discusses the results of a similar consideration of cell membrane differences and longevity within the human species:

Fatty Acid Profile of Erythrocyte Membranes As Possible Biomarker of Longevity:

Offspring of long-lived individuals are a useful model to discover biomarkers of longevity. The lipid composition of erythrocyte membranes from 41 nonagenarian offspring was compared with 30 matched controls. Genetic loci were also tested in 280 centenarians and 280 controls to verify a potential genetic predisposition in determining unique lipid profile.

...

Erythrocyte membranes from nonagenarian offspring had significantly higher content of C16:1 n-7, trans C18:1 n-9, and total trans-fatty acids, and reduced content of C18:2 n-6 and C20:4 n-6.

...

We concluded that erythrocyte membranes derived from nonagenarian offspring have a different lipid composition (reduced lipid peroxidation and increased membrane integrity) to that of the general population.

Note there again - reduced lipid peroxidation, as for the naked mole-rats, and therefore more resistant to oxidative stress. This is quite an interesting line of research, demonstrating some plausible indications of a structural contribution to longevity at the cellular level. I'm sure we'll be seeing more of this in the future, as research and debate continues.

A little while back, I took a look at using the big stick of materials science to manipulate biochemical states in the body - starting with efforts to build a better antioxidant:

Oxidative stress is believed to play a role in neurodegenerative diseases such as Alzheimer's and Parkinson's. Some of the symptoms of aging such as arteriosclerosis are also attributed to free-radical induced oxidation of many of the chemicals making up the body. Despite the broad role that oxidative stress plays in human disease, medicine has been limited in its development of treatments that counteract free radical damage and the ensuing burden of oxidative stress. In contrast, in the field of engineering, considerable effort has been developed to counter the effects of oxidative stress at the materials science level. ... Our initial results suggest that cerium oxide nanoparticles extend cell and organism longevity through their actions as regenerative free radical scavengers. Additional studies suggest that these nanoparticles are also potent anti-inflammatory agents. Although much work remains to be done in this realm, ceria nanoparticles hold high promise for future development of nanopharmacological agents to treat age related neurodegenerative disorders and inflammatory disorders.

This sort of initiative is but a tiny step on a very long path that leads to nanomedical robotics, artificial blood cells a thousand times better than the real thing, and even more impressive feats of engineering. But you have to start with what is presently possible. Some more on cerium oxide in this paper:

Treatment of Neurodegenerative Disorders with Radical Nanomedicine:

Here, we summarize the work on the biological antioxidant actions of cerium oxide nanoparticles in extension of cell and organism longevity, protection against free radical insult, and protection against trauma-induced neuronal damage. We discuss establishment of effective dosing parameters, along with the physicochemical properties that regulate the pharmacological action of these new nanomaterials. Taken together, these studies suggest that nanotechnology can take pharmacological treatment to a new level, with a novel generation of nanopharmaceuticals.

"Radical nanomedicine" means different things to different folk of course - anything from the mass-produced artificial blood cell nanomachines of the 2030s to next year's application of somewhat better and more useful nanoparticles. But the trend towards engineering your way out of unwanted biological conditions at the scale of molecules and cells is very welcome and to be encouraged. Engineers put the pieces together and get the job done - don't underestimate the power of that approach to problems.

One caveat on any work involving antioxidants is the evidence produced to date indicating that it matters greatly where your antioxidants do their work. Are they meandering around uselessly, far from the points at which oxidative stress is generated or causing damage? Are they interfering in the signaling mechanisms that actually use oxidizing molecules?

Rabinovitch's group genetically engineered mice to produce a natural antioxidant enzyme called catalase. The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years ...

We had differing hypotheses about where putting catalase might do the best in terms of the advantage to life and health of the mice," Rabinovitch explains. So they targeted the gene in three different places in the mouse cells - the cytoplasm, the nucleus - where they thought it might protect the all-important DNA of the cell - and the powerhouses of the cells, the mitochondria - where cells "burn" glucose for energy and churn out high levels of these oxidizing free-radicals. The mice that lived longest had the gene in their mitochondria.

Here's another approach indicating that it matters where you put your antioxidants:

Instead of gene therapy, Skulachev's group has found a viable biochemical strategy for effectively localizing ingested antioxidants in the mitochondria; clever.

But if you're a clever engineer, this is all just another challenge to build around.

Videoblogging, much like those newfangled social networks, is passing me by - but online video has proven to be a tremendously effective tool for reaching people, and more power to those who are making it work:

My End Aging Challenge is simple: Create and post a reply to this video on YouTube explaining why you support Dr. Aubrey de Grey's and the Methuselah Foundation's mission to end aging. I will donate $10 to the Methuselah Foundation for every video response. If you have the means, I also suggest that you offer in your video response to match me with a donation of your own for every video. After you shoot your video, follow this link to post your video reply.

Good show. If you want something done, no matter how daunting or large the task, the best way to go about it is to get out there and help make it happen. Put your shoulder to the wheel and lead by example. It matters not the size and weight of that wheel, as many hands make light work. It matters greatly that you show that the job exists, and that someone is willing to work at getting it done. Where is one willing worker exists, there will soon be more.

And so there are: see the responses to date over at YouTube. I encourage all of you with the inclination to create your own video messages to get out there and show your support. More from Kevin Dewalt here:

For those of you thinking about replying with a video I encourage you to have some fun and get creative with it. Why do you want to cure aging and live a few hundred more years? Do you want to visit the moon? Bring about world peace? Start a new career? Or perhaps you don’t care at all about yourself and just want to help relieve the suffering of others.

It is of a sea of many modest efforts that great storms arise. Want to change the world? Want a better, longer, healthier future? Then do something to help make it happen.

The latest Rejuvenation Research is available online. I've pointed out a couple of the more interesting papers already in the past weeks, as they appeared on PubMed:

• Cell Fusion and Regenerative Therapies
• Xenotransplanting New Mitochondria
• Can We Build a Longevity Therapy Atop Mitoptosis?

The theme for today is the way in which reality eventually starts to impinge upon unrealistic viewpoints. That is a point for hope, as there are a great many unrealistic viewpoints in the world that would hinder or halt longevity research, either directly or indirectly. Viewpoints like "the more regulation the better", "prove that you will do no harm at all before we'll let you move forward," or "let us redistribute all property and remove incentives for success and progress, for inequality for any is worse than death for all" spring to mind. In this latter context, "social justice" is a particularly pernicious phrase, being a shorthand for forceful redistribution of wealth by government fiat - institutionalized theft, aimed exactly at the point at which it will do the greatest damage to progress by removing incentives for success.

The world works this way: we can labor and trade to move everyone ahead, benefits for all and inequalities for all, or we can redistribute what presently exists - which at best leads to stagnation and no progress, and at worst becomes a repetition of Soviet era Russia and Eastern Europe. In both cases, inequality will be there - you can't kill it. The choice is whether it's inequality in comparative wealth or inequality in poverty, disease and rubble. Progress is absolutely dependent on freedom and the incentives of wealth earned through hard work and invention.

Fortunately, some folk are starting to realize that the stakes are much higher now than in the past. At one time you could be a parasite upon the body politic, propagating theories of no worth or that would cause great harm if enacted, without damaging your own prospects significantly. Now, however, we're talking about the difference between living to see the technologies of radical life extension - and thus living for a long, long time in good health - or dying because the development of those technologies is delayed. So we start to see papers like this:

Sufficiency, Justice, and the Pursuit of Health Extension:

According to one account of distributive justice, called the Sufficiency View, justice only requires that we bring everyone above some critical threshold of well-being and nothing more. This account of justice no doubt explains why some people believe it is unfair to invest scarce public funds into combating aging. In this paper I show why the sufficiency view is wrong. Furthermore, I argue that the real injustice occurs when we disparage or ignore all potential avenues of extending healthy living. We must be both ambitious and imaginative in our attitudes towards health extension.

You'll find analogous issues - and unhelpful, unrealistic viewpoints - within the scientific community. The most important of those have been set out at length in the past, such as in the essay "The Curious Case of the Catatonic Biogerontologists", or some of my past comments here at Fight Aging!:

The road to a cure for aging, like the road to a cure for cancer, has many waystations - each representating some level of treatment, some level of extended healthy life spans. Conservative gerontology ignores the existence of those waystations. Can you imagine a world in which cancer research proceeded that way, pure research with no funding invested in application and the development of therapies?

Fortunately, that state of affairs is somewhat on the way out - and not before time too. There's only so many years it could continue whilst watching vastly extended healthy life spans engineered in animals and work on calorie restriction science in humans. Sooner or later the same calculus applies: the personal risk of slowing down progress in healthy life extension is too great to hold onto unrealistic or unhelpful viewpoints.

Understanding and Tackling Aging: Two Fields Communicating (A Little) At Last:

A string of recent and forthcoming conferences, organized not only by those at the forefront of life-extension research but also by highly influential mainstream groups, have publicly endorsed the Methuselah Foundation's goal of defeating aging. The field of biomedical gerontology - the interface between biogerontology and geriatrics, where biological knowledge is focused on developing the geriatrics of tomorrow - is not a traditional component of gerontology, having been poorly appreciated by biogerontologists and geriatricians alike, but these developments show that it is rapidly taking its place at that table.

Some of the core strands of the modern day discussion of greatly increasing healthy human longevity through the advancement of medical science can be found in the first issue of Studies in Ethics, Law, and Technology:

As advances in medicine and the life-sciences continue offer the opportunity to “enhance” humans and other species, it becomes clear that the discussion of human enhancement raises questions in philosophy, religion, science, medicine, sociology, history, law, and many other disciplines.

There is something to be said for pushing aside the normal self-serving blather that populates this sort of region of ethical debate, colonizing the space with determined intent and hard science to support it. Chase out the bad with the good, and spread the meaningful debates that have taken place within the healthy life extension community: how, how long, what must be done to reach the goals of radical life extension.

Life Span Extension Research and Public Debate: Societal Considerations:

The pace of a given strand of scientific research, whether purely curiosity-driven or motivated by a particular technological goal, is strongly influenced by public attitudes towards its value. In the case of research directed to the radical postponement of aging and the consequent extension of healthy and total lifespans, public opinion is entrenched in a "pro-aging trance" - a state of resolute irrationality. This arises from the entirely rational attitude to a grisly, inevitable and relatively far-off fate: putting it out of one's mind allows one to make the most of what time one has, free of preoccupation with one's demise, and it is immaterial how irrational the arguments that one uses to achieve this are, e.g. by persuading oneself that aging is not such a bad thing after all.

As biotechnology increasingly nears the point where aging will no longer be inevitable, however, this studied fatalism has become a core part of the problem, making people reluctant to join the crusade to hasten that technology's arrival. An effective way to address this hesitation is to promote debate about the reasons people give for fearing the defeat of aging, most of which are sociological. Such debate exposes people to the glaring flaws in their own logic. Thus, the more the debate is sustained and promoted, the harder it is for those flaws to be ignored.

Medical Nanorobotics: Breaking the Trance of Futility in Life Extension Research:

Biogerontologist Aubrey de Grey has suggested that one of the reasons we as a society invest so little in research on combating aging is because we are in an intellectual trance. We think the effort will be futile: aging is immutable, so why try? A healthy skepticism can be a good thing but it is a major mistake to bet against the irresistible force of inexorable technological progress. Over the next few decades, nanotechnology will come to play a pivotal role in the solution to the problem of human aging. Medical nanorobotics, if it can be made to work, can unquestionably offer convenient solutions to all known causes of age-related damage and most likely can also successfully address any new causes of senescence that remain undiscovered today.

These two papers illustrate one of the core debates within the healthy life extension community - but it is a subtle debate, not addressed openly to the extent it deserves. Many people see activism in support of longevity science to be of limited necessity because they believe, I think, that general advances in technological capabilities drive entrepreneurial development cycles that drive public support for new uses. In effect, this is a belief in the robustness of a free market to explore every possible economically viable avenue for human betterment, and to leap upon newly viable avenues as soon as they arise.

My position is that this is probably the case in the long term. However, as always, it is easy to point out many economically viable and technologically possible projects that have not been started, in medicine or other fields, in the decades since they became viable. In addition to the economy of the free market, there exist economies of regulation, attention, understanding and philantrophic support - just because something is viable does not mean it will happen within your lifetime.

There of course is the crux of the matter. If we are to benefit from healthy life extension therapies, from medical technologies capable of repairing the damage of aging, progress must be rapid. Healthy life extension through scientific advancement is inevitable - but not for us, unless we get our act together.

A good last word from Ronald Bailey in the Cato Unbound discussion:

My vision of a future in which effective longevity treatments are available is one in which individuals get to choose to use them or not - no government gets to decide how long its citizens will be allowed to live. That would truly be tyranny. In the meantime, if Callahan chooses to go "gentle into that good night" I wish him well of it, but his job is to warn us the dangers he sees arising from radically extended lives and that’s all very well. He should allow the rest of us to ignore his advice and find out for ourselves whether he is right or wrong. Let us learn freely from trial and error as people always have done.

Freedom and choice are two vital portions of the fundament of a society worth living in. The freedom to be alive, and work on remaining that way, is the greatest of all freedoms - for without life, there is nothing: no possibilities, no human action, no building of a better world. We forget, in our comparative comfort, that to be able to choose to live another day in good health and do your part to move humanity into a better era is a luxury, considered in the grand scheme of human history.

We should value the freedom to remain alive and healthy far more so that we presently do, and thus rationally choose to work hard to extend that freedom for as many and as long as possible - in other words to work to defeat aging in addition to all other threats to life and health. This should go without saying, as an axiom of the human condition, and it is a great pity that that is not the case.

As you might have noticed, PubMed entries for papers in the next issue of Rejuvenation Research have been showing up of late. One of those papers looks at the prospects for harnessing mitoptosis as a longevity intervention, a topic guaranteed to catch my attention. What is mitoptosis? You can find a discussion thread on the topic with references over at the Immortality Institute. In essence, keeping it short, mitoptosis is the programmed destruction of mitochondria in your cells, a process analogous to apoptosis, or programmed cell death.

Mitoptosis: different pathways for mitochondrial execution

Mitoptosis was described as a sort of mitochondrial death program. It could be associated with both necrosis and apoptosis, although degenerating mitochondria are also found in autophagic vacuoles. It was demonstrated that several molecules might contribute to the remodeling and rearrangement of mitochondrial membranes, leading to mitochondria rupture and disruption. Here, we hypothesize that, at least in T cells, two main pathways of mitoptosis can occur: an inner membrane mitoptosis (IMM), in which only the internal matrix and cristae are lost while the external mitochondrial envelope remains unaltered, and an outer membrane mitoptosis (OMM) where only swollen internal cristae are detected as remnants.

But back to the Rejuvenation Research paper:

Exploring Overlooked Natural Mitochondria-Rejuvenative Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats

There is an imperative need for exploring and implementing mitochondria-rejuvenative interventions that can bridge the current gap toward the step-by step realization of strategies for engineered negligible senescence (SENS) agenda. Recently discovered in mammals, natural mechanism mitoptosis - a selective "suicide" of mutated mitochondria - can facilitate continuous purification of mitochondrial pool in an organism from the most reactive oxygen species (ROS)-producing mitochondria.

Mitoptosis, which is considered to be the first stage of ROS-induced apoptosis, underlies follicular atresia (a "quality control" mechanism in female germline cells that eliminates most germinal follicles in female embryos). Mitoptosis can be also activated in adult postmitotic somatic cells by evolutionary conserved phenotypic adaptations to intermittent oxygen restriction (IOR) and synergistically acting intermittent caloric restriction (ICR).

IOR and ICR are common in mammals and seem to underlie extraordinary longevity and augmented cancer resistance in bowhead whales (Balena mysticetus) and naked mole rats (Heterocephalus glaber). Furthermore, in mammals IOR can facilitate continuous stromal stem cells-dependent tissue repair. A comparative analysis of IOR and ICR mechanisms in both mammals, in conjunction with the experience of decades of biomedical and clinical research on emerging preventative, therapeutic, and rehabilitative modality - the intermittent hypoxic training/therapy (IHT) - indicates that the notable clinical efficiency of IHT is based on the universal adaptational mechanisms that are common in mammals. Further exploration of natural mitochondria-preserving and -rejuvenating strategies can help refinement of IOR- and ICR-based synergistic protocols, having value in clinical human rejuvenation.

To understand why this is interesting, you'll want to wander back in the Fight Aging! archives and read up on the mitochondrial free radical theory of aging. To cut a long story short, damaged mitochondria in a cell will breed more damaged mitochondria in that cell. Repeated over and over, this eventually causes a small but significant number of cells to export damaging free radicals throughout your body, causing great harm to health and life span over time. One focus of SENS and SENS-like research is to cut this process short at the "damaged mitochondria" phase. Eliminate the damaged mitochondria aggressively and often, and that portion of the aging process is gone.

Mitoptosis may be an existing mechanism that can be adapted to this end - though whether this is the case, and whether it is at the root of some exception longevity in the animal kingdom, remains to accumulate greater weight of evidence. For example, much of the recent published work on naked mole-rat biochemistry has suggested that crucial cellular components are more resistant to oxidative damage than those in other rodents, being built of a different mix of biochemicals, rather than being more aggressively recycled and repaired.

The greater the number of potential avenues of approach to each aspect of SENS, each facet of a true therapeutic approach to rejuvenation and the repair of aging, the better off we are. Competition drives the wheel of progress, and choice of approach is a sign of real progress in science. So I am always pleased to see new additions to the stable of potential future medical technologies.

A few unrelated papers caught my eye whilst winding my way through PubMed today. This first is an animal study building directly on the very rapid progress in understanding Hutchinson-Gilford progeria syndrome (HGPS), an accelerated aging syndrome.

Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation:

We recently reported that a protein farnesyltransferase inhibitor (FTI) improved several disease phenotypes in mice with a HGPS mutation (Lmna(HG/+)). Here, we investigated the impact of an FTI on the survival of Lmna(HG/+) mice. The FTI significantly improved the survival of both male and female Lmna(HG/+) mice. Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS.

This is intervening directly in the mechanisms left broken and malfunctioning by Lamin A (Lmna) mutations. You'll find a more clear explanation of the involvement of farnsylation in an earlier, similar mouse study:

Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei.

The point of interest to all of the rest of us in this research is that cells in the normal elderly appear to be suffering from the same issues. A working therapy for progeria is likely also a therapy of benefit to those suffering from ordinary aging processes.

Switching topics: it's often the case that studies in laboratory animals are criticized for using breeds that are far from wild-type animals, having been bred for generations in the absence of selective pression, wild-type conditions, and so forth. That is a valid criticism when dealing with complex biological systems of many variables, so it is good to see someone filling in the gaps, as in this paper:

Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes:

Dietary restriction is known to promote longevity in a variety of eukaryotic organisms. Most studies of dietary restriction have been performed on animals bred for many generations under conditions that differ substantially from their natural environment, raising the possibility that some apparent beneficial effects of dietary restriction are due to adaptation to laboratory conditions. To address this question in an invertebrate model, we determined the effect of dietary restriction by bacterial deprivation on life span in five different wild-derived Caenorhabditis elegans strains and two strains of the related species Caenorhabditis remanei. Longevity was enhanced in each of the wild-derived C. elegans strains, in most cases to a degree similar to that observed in N2, the standard laboratory strain. Both strains of C. remanei were substantially longer lived any of the C. elegans isolates, produced larger brood sizes, and retained the ability to produce offspring for a longer period of time. Dietary restriction failed to increase mean life span in one C. remanei isolate, but significantly increased the maximum life span of both C. remanei strains. Thus, we find no evidence that adaptation to laboratory conditions has significantly altered the aging process in C. elegans under either standard or food-restricted conditions.

There you have it.

Switching topics once more, this last paper on the origins of osteoporosis caught my eye more for the sentiments of the researchers than for the contents:

Evolution, Aging, and Osteoporosis:

We suggest that future osteoporosis therapy will likely focus on prevention of aging in general as a means to prevent the development of osteoporosis.

I can't overemphasis how much of a sea change it is to see more of this kind of talk in the scientific community. This first decade of the 21st century is a real turning point for aging research, wherein the mainstream slowly realigns itself to to goal of healthy life extension, while the cutting edge is running ahead with the defeat of aging in mind. We live in interesting times.