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.

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

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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.

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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.

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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.