Commentary on various recently published research relevant to the SENS view of biotechnology to repair and reverse aging appears as an occasional feature at the journal Rejuvenation Research. The latest is open access, so take a look at the PDF format paper, containing commentaries such as this one on a method of wrapping enzymes in polymer nanocapsules to ensure their delivery to specific locations within cells or the body:

The accumulation of recalcitrant waste substances in cells' lysosomes is implicated in a wide spectrum of aging-related diseases, including atherosclerosis, age-related macular degeneration (AMD), and many others. Being one of the clearest examples of the build-up of "junk" in aging bodies, it is expected that means to degrade lysosomal waste will be among the first rejuvenation biotechnologies to reach clinical application.

Indeed, the required development time before an effective therapy can be deployed is expected to be so brief that SENS Research Foundation devotes a substantial portion of its budget to identifying and refining enzymes for just this purpose. However, this tight schedule poses a specific problem; it is quite probable that hydrolases effective, for example, against 7-ketocholesterol (the dominant "junk" molecule in atherosclerotic plaque) or A2E18 (predominant in AMD) will be ready for clinical use before safe and effective somatic gene therapy becomes available.

It will therefore be necessary to introduce these garbage-clearing enzymes into patients directly, rather than by genetically engineering the recipient's cells to produce them - an approach termed enzyme replacement therapy, currently in widespread clinical use to treat congenital lysosomal disorders. Of course, enzymes introduced into the body by such methods cannot be replaced once degraded (a particularly rapid fate in the harsh conditions of the lysosome), necessitating regular infusions to maintain their function. The polymer-coating method described in this study enhances the hardiness of the enzymes thus treated, and might be reasonably expected to thus appreciably reduce the required frequency of reintroduction, and/or minimise the dosages required (and hence any side-effects).

Link: http://online.liebertpub.com/doi/pdf/10.1089/rej.2013.1426

Source:
http://www.fightaging.org/archives/2013/03/comments-on-recent-research-relevant-to-combating-aging.php

This paper examines some aspects of aging in the liver, giving a general review in the course of getting to a discussion on immune system changes that occur in aging and their influence on the liver. Note the importance of a buildup of unwanted protein byproducts inside liver cells, something that occurs due to the progressive failure of cellular housekeeping components known as lysosomes. You might recall that researchers reversed aspects of liver aging in mice a few years back by boosting lysosomal activity, so as to counteract some of the usual decline.

Although the human liver is not unscathed by the process of aging, the changes it undergoes are minor compared with other organ systems. It has been ascertained that there are no liver diseases specific to advanced age. However, the clinical course and management of liver diseases in the elderly may differ in several aspects from those of younger adults.

Human and experimental studies suggest that, in comparison with other organs, the liver ages fairly well. Aging is however associated with a variety of morphological changes in the liver, but their underlying mechanisms are still unclear. The liver progressively shrinks by 20-40% during the course of a human life, and there is a concomitant age-related decrease in liver volume. The classic gross appearance of the liver in the elderly is known as "brown atrophy", and the brown is due to an accumulation of highly oxidized insoluble proteins, known as lipofuscin, stored into hepatocytes. These accumulations of highly cross-linked protein are thought to relate to chronic oxidative stress and a failure to degrade damaged and denatured proteins. Increasing evidence suggests that lipofuscin interferes with complex cellular pathways.

One of the most important age-related changes in liver function observed in animal models is a significant decrease in regenerative capacity of the liver, but not in the capacity to restore the organ to its original volume. [It] has also been shown that aging is associated with multiple changes in. Elderly humans secrete less bile acid, have increased biliary cholesterol levels, and show an increased oxidative stress that is mainly attributable to a reduced capacity to eliminate metabolically generated superoxide radicals as efficiently as before. The reduction in hepatic blood flow during aging reduces the metabolism of rapidly cleared drugs. Aging of the liver is also associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins.

Link: http://dx.doi.org/10.1186/1742-4933-10-9

Source:
http://www.fightaging.org/archives/2013/03/a-look-at-the-aging-liver.php

Gerontocracy:

Government by a council of elders. Government by old people.

There are many knee-jerk reactions to the prospect of greatly increased healthy human life spans, most based on mistaken beliefs regarding the technologies needed, or mistaken beliefs regarding the way the world actually works - economics, human action, incentives. Some people believe that longer lives will result in stagnation, which is actually one of the more ridiculous and improbably outcomes once you start to pick it apart in any detail. Human society is restless and changeable on timescales far shorter than current lifespans, and the reasons why are rooted in day to day human nature. Our ambitions operate on a horizon of a few years, and that wouldn't change all that much were we to live for centuries. We are driven to influence the world today, now, regardless of the years that lie ahead of us. So the fashions of this year are gone by the next. The idols of popular culture rise and fall with rapidity. The political and business leaders of this decade are gone in the next, displaced by peers. Even corruption and revolution on a grand scale are usually only a matter of a few decades, not lifetimes.

Nonetheless, rationality rarely prevails in knee-jerk reactions - so folk think of stagnation, even in the midst of this boundlessly energetic society we live in, packed wall to wall with constant, ongoing change. A subset of these beliefs on human longevity and stagnation involve the nebulous fear of a future gerontocracy, the rise of a self-perpetuating ruling elite of ageless individuals. Funnily, this is often voiced by people who are, unlike myself, perfectly comfortable with today's Western governments. I say funnily because I have to ask: are not our present societies already gerontocracies? Isn't any civilized society a gerontocracy? Who has had the most time to gather connections, a network, and make good use of them? The old. Who has had the most time to gather resources and invest them? The old. Who has had to most time to become truly talented and sought after? The old. Who has had the most time to work their way through a social hierarchy to challenge its existing leaders? The old. Where then will the elite and the leaders tend to arise? From the old.

Take a look at who just runs and influences companies, governments, knitting circles, successful non-profit initiatives, extended families, and so on and so forth for every human endeavor. Young leaders exist, but they are a minority among the ranks of the old. This is the natural state of affairs for any society that possesses enough technology to make thought and craft more important than strength and vigor.

All that is terrible in our present societies lies in the growing centralization of power, not the chronological age of those eagerly engaged in furthering the road to serfdom and empire. Even as power is centralized, there is still a year by year turnover of figures - even in the most defensible and corruptly secure positions of power and influence. They are largely kicked out by some combination of their peers and the mob in the sort of political anarchy that exists at the top, above the laws made for the little people. It is the rare individual who can stick it out long enough to be removed by the infirmities of age, even now, in this age of human lives that are all too brief in comparison to what is to come.

But back to the point. We live in a gerontocracy, and so did most of our ancestors. Yet change still happens just as rapidly as in past centuries when fewer people lived into later life in the sort of good shape they can manage today. Fear of some sort of comic-book gerontocracy emerging in the future seems, frankly, somewhat silly. But here is an article on the topic that treats such fears with a little more respect than I'm inclined to deploy.

http://io9.com/will-old-people-take-over-the-world-458358266

The human lifespan is set to get increasingly longer and longer. And it's more than just extending life - it's about extending healthy life. If we assume that the aging process can be dramatically slowed down, or even halted, it's more than likely that the older generations will continue to serve as vibrant and active members of our society. And given that seniors tend to hold positions of power and influence in our society, it's conceivable that they'll refuse to be forced into retirement on the grounds that such an imposition would violate their human rights (and they'd be correct in that assessment).

In turn, seniors will continue to lead their corporations as CEOs and CFOs. They'll hold onto their wealth and political seats, kept in power by highly sympathetic and demographically significant elderly populations. And they'll occupy positions of influence at universities and other institutions.

So I asked James Hughes how society could be hurt if an undying generation refuses to relinquish their hold on power and capital. "Again, the question should be, how is society hurt when small unaccountable elites control the vast majority of wealth?," he responded. The age of super-wealthy is pretty immaterial, he says, especially when most of the people in their age bracket will be as poor and powerless as younger cohorts.

Hughes also doesn't buy into the argument that radical life extension will result in the stagnation of society. If anything, he thinks these claims, such as risk-aversion and inflexibility, smack of ageism and simple-minded futurism. "Seniors' brains continue to make stem cells," says Hughes, "and when we are able to boost neural stem cell generation in order to forestall the neurodegeneration of aging, older people will become as cognitively flexible as younger people."

As noted in my comments above, the historical record shows that people at the top are not all that good at staying at the top for extended periods of time. There are always outliers, but they are rare in comparison to the vast majority of leaders and the famous who are just part of the churn, coming and going, displaced and quickly forgotten once their few years are done. The top of a pyramid is a challenging place to stand.

Source:
http://www.fightaging.org/archives/2013/03/we-already-live-in-a-gerontocracy.php

An open access review on the topic of aging and longevity, largely focused on mainstream work aimed at producing ways to gently slow aging by metabolic manipulation:

Aging drives disease. Nearly every major killer in developed countries shares a common feature: your risk of getting the disease increases dramatically as you get older. For example, the likelihood of being diagnosed with Alzheimer's disease doubles every five years after the age of 65. A similar kind of relationship can be seen for most types of cancer, heart disease, diabetes, kidney disease, and many others. What is it about getting older that simultaneously increases risk for all of these disorders? Are there common molecular changes that cause an organism to switch from youthful and healthy to aged and infirm? Can we intervene in this process to do something about it? These are some of the big questions that scientists who study the biology of aging are interested in answering.

The perspective that most age-related disorders share a common underlying biology is a departure from traditional biomedical science, one that potentially offers a more powerful approach towards improving human health. Rather than focus on curing the individual disease, interventions that target the molecular processes of aging can simultaneously delay the onset and progression of most age-related disorders. Such an intervention is predicted to have a much larger effect on life expectancy than can be attained by treating individual diseases. This is because even if one disease is cured, the relationship between age and all the other disorders of aging still holds. For example, it has been estimated that curing cancer will lead to only a 3-5 year increase in survival for an average 50 year-old woman, while slowing aging to an extent that is routine in laboratory organisms has about a 5-10-fold greater impact on life expectancy.

Importantly, these added years from slowing aging are spent largely free from chronic disease and disability, while the relatively small gains in survival by curing cancer (or any other individual disease of aging) are still associated with the inevitable age-related declines in function of every other bodily system. This concept of extending the period of life spent free from chronic disability and disease, referred to as healthspan, is a critically important idea in the field of aging-related research.

Link: http://dx.doi.org/10.12703/P5-5

Source:
http://www.fightaging.org/archives/2013/03/considering-longevity-aging-and-medical-science.php

What is aging? This deceptively simple question will garner you lengthy answers from the scientific community - many different lengthy answers, as it happens, some of which are even long enough to take the form of entire, complete books. There is a lot to be said on aging, and vast repositories of data, and yet there remain numerous different camps with different detailed definitions of aging - it's cause, its progression, and how best to build therapies that might slow or reverse aging.

So you have the definition put forward by Michael Rose and colleagues, or the hyperfunction theories that seem to be gaining ground among researchers of the small programmed aging camp, or the collection of mainstream views - many different interpretations and variants - that paint aging as a matter of accumulated damage.

And that is just on the matter of causes and mechanisms. The territory becomes much more of a jungle once you start down the path of asking whether aging is a disease, or whether it is a bad thing, or whether should be treated and ameliorated through medical science. Believe it or not there remain numerous researchers in the field who believe that aging should be studied but not treated, slowed, or reversed, despite the suffering and death it causes. Here is an open access opinion piece on this topic from Aubrey de Grey, via the Rejuvenation Research journal.

The desperate need for a biomedically useful definition of "aging" (PDF)

Surely everyone who studies the biology of aging fundamentally agrees on what it is they are studying, even if they may prefer somewhat different terminology to define it? I'm afraid you'd be wrong. Disagreement within the field about what aging really is and is not is very far from purely semantic, and the substance of those disagreements leads to profound differences of opinions concerning both what research gerontologists should prioritise and how they should communicate their work to others.

First: is aging a disease? Some gerontologists will just tell you "No, it is separate from age-related diseases". Some will say "No, but it is a risk factor for age-related diseases". Some will say "No, it is the set of precursors of the age-related diseases". Some will say "Yes, it is the set of precursors of the age-related diseases"! Self-evidently, whether X is a Y depends not only on the definition of X but also on the definition of Y, so one might excuse this chaos on the basis of a failure to agree on what is and is not a disease - and there is indeed no such agreement. But it gets worse.

Is aging a thing that is amenable, in principle, to medical intervention? Not if you believe the protestations of such eminent gerontologists as Bruce Carnes and Jay Olshansky, who in a recent paper critiquing (I employ classic British understatement in my choice of words here) various colleagues' work made, in spite of reviewers' efforts to educate them, the assertion that "What Wilmoth fails to acknowledge is that in order to reduce death rates at advanced ages to zero or close to it, our biology would need to be modified" (my emphasis). This sort of language, without stating explicitly that medicine can never maintain the body in a state of health so youthful that death rates will be vastly lower than today, unequivocally seeks to convey that view. So, do other gerontologists agree? Indeed they do not: if any evidence were needed, I may merely cite the fact that almost every mainstream conference on the biology of aging these days has a subtitle referring to delaying or even reversing aging.

Finally, is aging even a bad thing? At least here we find broad consensus among biogerontologists - those who study the biology of aging (though there are a few exceptions). But the same does not apply to all gerontologists: those whose field is more on the clinical, or the sociological, side tend to be among the most viciously and vocally opposed to any talk (let alone action) concerning actually doing anything about aging. As an example, a very senior (and, I am afraid to say, highly influential) clinical gerontologist from Canada recently wrote to me as follows: "I do not wish in any way shape or form to have my name associated with anti-aging medicine, regenerative or restorative medicine or some such". No kidding. I will be interested to discover, at some point, whether she is willing to defend that view publicly.

It should by now be apparent that there is a bit of a problem. Let me emphasise, however, just how much of a problem. At present, translational biogerontology (alternatively, biomedical gerontology) commands an absolutely minuscule proportion of the medical research budget of any industrialised nation. Why? Simply because the idea that postponing aging is a feasible and valuable goal, both socially and economically, has failed - despite the best efforts of many biogerontologists over many decades - to gain any significant traction among funding bodies.

I contend that gerontologists' muddled thinking outlined above concerning what aging really is is actually the number one reason for this failure.

Source:
http://www.fightaging.org/archives/2013/03/in-search-of-a-useful-scientific-definition-for-aging.php

A paper on the life span of neurons in relation to their host organism was published earlier in the year and has been doing the rounds in recent days:

Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits.

In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longer-living host.

This is indeed the barnstorming age of biotechnology. As you might already know, we humans possess many nervous system cells that we were born with and which will last our entire lifetime. This is in contrast to much of the rest of our body where cells are replaced over various timescales, from years for some tissues to days for others. It is even that case that some individual macromolecules within brain cells last unchanged throughout life - not just the cell remaining on station for a lifetime, but some of its fundamental building blocks as well.

The fact that many neurons are never replaced is the source of a range of frailties and age-related conditions that result from increasing damage or buildup of unwanted metabolic byproducts in these long-lived cells. Nonetheless, it seems very reasonable to expect that our neurons are capable of outlasting the present limits of human life span, given the fact that it isn't neurodegeneration that kills supercentenarians - their brain cells are, by and large, still marching along even in the final years. No, death by aging is a systems failure, not a timed simultaneous failure of all the components that make up that system.

Is work on rodent neurons quoted above particularly relevant, or does it change anything? I is interesting, but I think that the answer is "no." We already know that developing the means to repair existing neurons in the brain is necessary. Boosting the rate at which new neurons are created will almost certainly be helpful, but a good portion of the brain stores the data that is the mind - those neurons and their encoded data have to be preserved and maintained, not replaced wholesale. So here it seems to me that knowing that neurons have a longer shelf-life doesn't change anything in the game plan.

Further, there's no guarantee that the longer neuron shelf-life in rodents has any great relevance to human cells. The analogous human study might be to pull long-lived neurons from a supercentenarian and culture them in a 3-D engineered environment that replicates their home tissue as closely as possible. Then you wait - for a fair number of decades. By the time that experiment comes to any interesting result, the whole issue will be moot. Either we will be dead, or SENS-like rejuvenation biotechnologies will be developed, and in either case researchers will already know so much more about cellular biology that they will be long past the point of answering all the questions that the study might help to resolve.

Source:
http://www.fightaging.org/archives/2013/03/neurons-can-outlast-their-host-in-at-least-one-species-but-is-that-at-all-relevant.php

One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills.

Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target.

A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end:

Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted.

With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs.

In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo.

Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them.

Link: http://www.sens.org/research/research-blog/project-break-aging-arteries-free

Source:
http://www.fightaging.org/archives/2013/03/sens-research-foundations-age-breaker-research-programs.php

Here is a piece to act as fuel for people who like to argue policy and don't look much beyond the now. I think this is chiefly interesting for the potential support it gives to lifestyle differences between the genders as a noteworthy contributing cause to the fact that women live longer. Otherwise, it reinforces the point that differences in life expectancy at birth between regions or over time is not all that relevant to the intersection of medicine and aging - more attention should be given to statistics for life expectancy at 50 or 60.

Higher mortality rates among Americans younger than 50 are responsible for much of why life expectancy is lower in the United States than most of the world's most developed nations. The research [found] that excess mortality among Americans younger than 50 accounted for two-thirds of the gap in life expectancy at birth between American males and their counterparts and two-fifths between females and their counterparts in the comparison countries.

Most of the excess mortality of those younger than 50 was caused by noncommunicable diseases, including perinatal conditions, such as pregnancy complications and birth trauma, and homicide and unintentional injuries including drug overdose, a fact that she said constitutes a striking finding of the study. "These deaths have flown under the radar until recently. This study shows that they are an important factor in our life expectancy shortfall relative to other countries."

You get further in life by comparing what you have to what is possible, not with what other people have. But relativism of status, circumstances, and possessions is deeply set into the human mind. It's ever a struggle to get people to look beyond what is to see what might be.

Link: http://www.upenn.edu/pennnews/news/penn-study-links-us-mortality-rates-under-age-50-us-life-expectancy-lagging-other-high-income-c

Source:
http://www.fightaging.org/archives/2013/03/on-mortality-rates-and-life-expectancy.php

Studies suggest that longer life expectancy runs in families to some degree - though it is always the case that what you get in the genetic lottery can be squandered by poor lifestyle choices. Gene variants appear to be more important in determining remaining life expectancy at older ages than at younger ages, which is another way of saying much the same thing. Either way, the end result will be the same until we can build rejuvenation biotechnology.

According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non-centenarian parent provides a further advantage.

A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies.

The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23403041

Source:
http://www.fightaging.org/archives/2013/03/another-study-on-inheritance-of-human-longevity.php

Calorie restriction produces a general slowing of the progression of degenerative aging and creates sweeping changes at all levels of metabolism. Thus it should not be a surprise to find protective effects no matter how deep you dive into the biochemistry of calorie restricted laboratory animals. Here's one of the many more detailed examples, looking at the abundances of receptors known to be important in brain function:

The effects of aging and long-term caloric restriction, on the regulation of neuropeptide Y (NPY) Y(1), Y(2) and Y(5) receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12 months.

In the brain of 3-month-old AL rats, the distribution and densities of Y(1), Y(2) and Y(5) receptors were in agreement with previous reports. In the brain of 20-month-old AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed.

In contrast, caloric restriction had multiple effects. It induced specific decreases of Y(1)-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y(2)-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y(1)-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y(2)-receptor densities in the CA2 subfield of the hippocampus.

These results indicate that caloric restriction not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23410741

Source:
http://www.fightaging.org/archives/2013/03/calorie-restriction-protective-of-specific-brain-mechanisms.php

Since it is possible to take a patient's cells and generate a very large number of immune cells, far more than the patient would ever have normally, and since it's possible to make some alterations to immune cells to make them more effective, why not do this? It's probably the case that even generally healthy older people would benefit from a regular infusion of large numbers of their own immune cells, or even donor cells, given the way in which the immune system declines with age, but under present medical regulation you'll only ever see it deployed as a treatment for late stage disease:

[Researchers] have successfully infused large numbers of donor T-cells specific for a key anti-leukemic antigen to prolong survival in high-risk and relapsed leukemia patients after stem cell transplantation. [T-cells were] taken from a donor, programmed in the lab to recognize the Wilm's Tumor Antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote anti-leukemic activity. The WT1 protein is overexpressed in leukemias and is in part responsible for why the cells have become leukemic.

All of the patients [received] adoptively transferred infusions of billions of enhanced CD8 cytotoxic T-cell clones. They were considered at high risk of death because they had already relapsed and/or had a poor prognosis due to unfavorable characteristics of their leukemia.

Four of the 11 patients in the trial received infusions of T-cells that targeted WT1 and were generated in the presence of IL-21. One had detectable relapsed disease and entered complete remission shortly after the T-cells were infused. All four survived after T-cell therapy without relapse for more than 30 months without suffering graft-vs.-host-disease and required no additional anti-leukemic treatment, according to the study.

Among the seven patients who received infused T-cells generated without the presence of IL-21, two showed direct evidence of anti-leukemic activity, including one patient with advanced progressive disease who had a temporary response.

Link: http://www.sciencedaily.com/releases/2013/02/130227151248.htm

Source:
http://www.fightaging.org/archives/2013/02/infusing-large-numbers-of-immune-cells-as-a-therapy.php

One of the more depressing consequences of degenerative aging is the pervasive ageism of our societies. It is taken as read that the old are worth less than the young, are less deserving, their wants and desires less meaningful, their rights to the pursuit of life and happiness weak to nonexistent. This is something that even the old themselves are largely sold on, one of those shared cultural myths that isn't so much taught as absorbed and spread invisibly, clinging on to every story and conversation as a cloud of assumptions and implicit judgments of value.

The value of a life diminishes with age, or so goes the belief - and as we are creatures of hierarchy and position, it's a short step from there to trampling on the old in any number of ways. If the young get to it before the old trample themselves, in any case. Ageism is as much a matter of people telling themselves that they are of little value as anything else.

Below you'll find the rather gloomy viewpoint of a near-70-year-old, informed by the Tithonus Error, the incorrect view that extended life achieved through biotechnology will result in more and increasingly decrepit old age rather than more vigor and youth as is in fact the case. As Aubrey de Grey asked in a recent editorial, why do people completely ignore what the research community says on this topic? Or for that matter, why do they ignore history? The incidental lengthening of human life achieved over the past two centuries through general improvement in medical technologies has been an extension of youth rather than an extension of old age.

The public doesn't stick its head in the sand in the same way for heart disease or Parkinson's research. One might well ask why this happens for aging. Here is a telling sort of a quote when it comes to self-value:

Please welcome the 150-year-old woman

Maybe it's time to ask medical science to shut it down already. Maybe there's something about our bodies that has a sell-by date. Maybe we're not supposed to stare vacantly into space while eating up money and time. There is so much else for science to be doing. There are the cancers that get people in their 30s and 40s and 50s. There are orphan diseases, with not enough sufferers to warrant full-scale research efforts. There are those wounded in war and the challenges they present. Surely all of these matters deserve more attention than how to make sure a 110-year-old person lives to be 125.

I speak myself as someone on the cusp of 70. I am not fond of disease and decay, and I think medical science should be all over finding cures for whatever I've got. But I have visited nursing homes, and seen the floors of lost people, technically alive but not aware of their surroundings, bewildered by everything.

Is this really a vision of the future that you want to have, or you want your parents to have? The geriatric lifestyle seems an awful lot like just taking up space. That's not really anybody's ambition for their end-of-life situation, but it happens anyway. People run out of friends and loved ones; they disappear from memory and from society. And yet they survive.

The goal of longevity science is to roll out ways to slow, halt, and reverse aging: making people healthy and physiologically younger for longer, not older and increasingly frail for longer. Researchers are all agreed on that goal, and say as much in their publications and to the press. Yet as you can see, there remains something of a disconnect - the message has yet to come through to the public at large.

Source:
http://www.fightaging.org/archives/2013/02/the-old-have-been-persuaded-to-see-themselves-as-worthless.php

The Breakthrough Prize in Life Sciences is a new and narrowly focused Nobel-like initiative launched by a noteworthy Russian entrepreneur in collaboration with some of the high net worth individuals that the California start up community has produced over the past decade. The tagline is much as follows:

Breakthrough Prize in Life Sciences is founded by Art Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner to recognize excellence in research aimed at curing intractable diseases and extending human life. The prize is administered by the Breakthrough Prize in Life Sciences Foundation, a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career.

Note that "extending human life" in the middle there. It looks like we'll have to wait to see whether the ongoing prize initiative will place any real emphasis on that goal, however. The eleven inaugural awards of $3 million each went to researchers who don't have a great deal to do with longevity research.

Eleven scientists, most of them American, were scheduled to be named on Wednesday as the first winners of the world's richest academic prize for medicine and biology - $3 million each, more than twice the amount of the Nobel Prize. The award, the Breakthrough Prize in Life Sciences, was established by four Internet titans led by Yuri Milner, a Russian entrepreneur and philanthropist who caused a stir last summer when he began giving physicists $3 million awards.

Cancer and its mechanisms form the dominant theme in this first set of awards. In some cases the scientists' work touches on aging, such as the telomere research of Titia de Lange, but then so do a great many other line items - it's quite possible to run a very successful career as a telomere researcher without contributing towards efforts to extend human life by intervening in the aging process.

That said: this is an entirely sensible and rational effort. In the long view the only thing that really matters is progress in technology - not money, not politics, not the chatter of the masses, but technology. What was built and invented, and how fast it arrived. What use is money if you can't use it to change the world for the better? The best way to do that today is through spurring progress in biotechnology. The greatest gains for all humanity, wealthy and poor alike, over the decades to come will be attained through advances derived from the life sciences: better medicine, longer lives, and ultimately the defeat of degenerative aging.

This Nobel for the 21st century is a step in the right direction and to be applauded. It is encouraging to see that the right ideas about medicine, biotechnology, and the near-term promise of radical, transformative applications are percolating through the community of high net worth individuals - that some are seeing clearly enough how and why they can make a difference. Still, the Breakthrough Prize is a drop in the bucket of what could be accomplished should any similarly-sized group of billionaires decide to devote a few hundred million dollars towards developing rejuvenation biotechnologies of the sort specified in detail in the SENS plan.

Source:
http://www.fightaging.org/archives/2013/02/noting-the-inaugural-breakthrough-prize-awards.php

One major branch of future progress in stem cell therapy will discard transplantation of cells in favor of manipulating the signals that tell local cells what to do - which is generally what the transplanted cells are actually doing anyway. This will become more effective as researchers gain a better understanding of the intricacies of cell signalling relevant to growth and repair, but here is an early example of what can be done with this sort of approach:

In the first human study of its kind, researchers activated heart failure patients' stem cells with gene therapy to improve their symptoms, heart function and quality of life. [Researchers] delivered a gene that encodes a factor called SDF-1 to activate stem cells like a "homing" signal.

SDF-1 is a naturally occurring protein, secreted by cells, that guides the movement of other cells. Previous research [has] shown SDF-1 activates and recruits the body's stem cells, allowing them to heal damaged tissue. However, the effect may be short-lived. For example, SDF-1 that's naturally expressed after a heart attack lasts only a week. In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients' stem cells. Study participants' average age was 66 years.

Researchers injected one of three doses of the SDF-1 gene [into] the hearts of 17 patients with symptomatic heart failure and monitored them for up to a year. Four months after treatment, they found: 1) Patients improved their average distance by 40 meters during a six-minute walking test. 2) Patients reported improved quality of life. 3) The heart's pumping ability improved. 4) No apparent side effects occurred with treatment.

"We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level. They still had evidence of damage, but they functioned better and were feeling better." Researchers are now comparing results from heart failure patients receiving SDF-1 with patients who aren't. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years.

Link: http://www.eurekalert.org/pub_releases/2013-02/aha-sc021813.php

Source:
http://www.fightaging.org/archives/2013/02/an-example-of-the-future-of-stem-cell-therapies.php

It is pleasing to see this sort of article emerging from a university publicity group - a part of the necessary trend within the scientific community towards making it acceptable and desirable to talk about extending human life through biotechnology. The silence of the research community on this topic across past decades was very harmful to the prospects for progress and funding in the field of aging research and longevity science.

That said, it is problematic that the vast majority of resources and researchers presently focus on modestly slowing aging rather than trying to repair and reverse the causes of aging. Based on what we know today, it is probably harder to safely adjust metabolism to slow down aging than it is to repair the root causes of aging to restore a metabolism back to its youthful state. Further, slowing aging is of no use to old people, whereas repair based approaches are useful - and given that people in middle age today will be old by the earliest possible time that therapies might emerge, it won't be all that great if all those therapies can do is slow down the progression of aging.

So more work on SENS and similar repair-based strategies, and less fiddling around with calorie restriction mimetics, longevity genes, and the like, is what we need to see if there is to be an effective near-term lengthening of human life. That result has to be based on rejuvenation, not slowing of aging.

Evidence is accumulating that not only is it possible to slow down aging, but that by doing so the onset and progression of multiple age-related diseases can be delayed. "Slowing aging should increase both lifespan and healthspan - the period of life spent in relatively good health, free from chronic disease or disability. A shared feature of most medically relevant diseases is that your risk of dying from them increases dramatically as you get older. Unlike traditional approaches, which tend to focus on a specific disease, targeting the aging process itself has a much greater potential to improve human health."

Many experts in the biology of aging believe that pharmacological interventions to slow aging are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by mTOR, a protein that controls cell growth. "Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow aging and reduce age-related pathologies in humans."

Link: http://www.washington.edu/news/2013/02/21/drugs-to-slow-aging-are-a-matter-of-when-not-if/

Source:
http://www.fightaging.org/archives/2013/02/drugs-to-slow-aging-are-a-matter-of-when-not-if.php

Calorie restriction slows the progression of near all measurable aspects of degenerative aging, and improves near all measures of health. It extends life by up to 40% in mice, and one of the interesting challenges for the study of metabolism is to explain the mechanics of how it can improve health so greatly in humans while failing to extend life to the same degree as it does in shorter-lived mammals. There is a good evolutionary explanation for this phenomenon; the expected length of a naturally occurring famine is the same whether you are a mouse or a man, and thus life span changes in response to famine must be more dramatic in a shorter lived species in order to have a decent chance of surviving it to reproduce. But that doesn't tell us how it happens under the hood.

Some of the triggers for the metabolic changes of calorie restriction involve sensing protein levels. Maintaining the same calorie intake while reducing dietary protein levels captures some fraction of the full effects of calorie restriction, with methionine seemingly the most important triggering protein.

Here a noted calorie restriction researcher shows protein restriction to slow the progression of a mouse model of Alzheimer's disease - which is pretty much the expected result, given what we know so far of how the effects of protein restriction map to those of calorie restriction:

Low-protein diet slows Alzheimer's in mice

Mice with many of the pathologies of Alzheimer's Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months. Mice at advanced stages of the disease were put on the new diet. They showed improved cognitive abilities over their non-dieting peers when their memory was tested using mazes. In addition, fewer of their neurons contained abnormal levels of a damaged protein, called "tau," which accumulates in the brains of Alzheimer's patients.

Upcoming studies [will] attempt to determine whether humans respond similarly - while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease. "We had previously shown that humans deficient in Growth Hormone receptor and IGF-I displayed reduced incidence of cancer and diabetes. Although the new study is in mice, it raises the possibility that low protein intake and low IGF-I may also protect from age-dependent neurodegeneration."

The team found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1's effects by binding to it. IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans. Exploring dietary solutions to those diseases as opposed to generating pharmaceuticals to manipulate IGF-1 directly allows Longo's team to make strides that could help sufferers today or in the next few years.

"We always try to do things for people who have the problem now. Developing a drug can take 15 years of trials and a billion dollars. Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment - understanding that effective interventions in mice may not translate into effective human therapies."

You might take note of those last remarks as indicative of one of the ways in which regulation steers researchers towards deliberately aiming to produce marginal benefits rather than revolutionary advances - slowing the pace of progress and shutting down promising avenues of medical science before they even get started.

Source:
http://www.fightaging.org/archives/2013/02/protein-restriction-slows-progression-of-mouse-model-of-alzheimers-disease.php

Researchers are here working on an injectable gel scaffold material that appears to improve regeneration of heart damage:

[Researchers have] developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of myocardial infarction. The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks.

[The researchers] developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity.

Link: http://blogs.nature.com/spoonful/2013/02/injectable-gel-repairs-damage-after-heart-attack-in-pigs.html

Source:
http://www.fightaging.org/archives/2013/02/injectable-scaffold-gel-to-spur-heart-regeneration.php

Here is a great opportunity for undergraduate and recently graduated life scientists: a chance to intern this coming summer at the SENS Research Foundation, an ambitious and well-connected organization that funds work on repairing the cellular and molecular damage that causes aging. If this is an area of applied medical biotechnology that interests you - and it should, as today you stand at the ground floor of a field that will expand in decades ahead to dwarf present behemoth research communities like the cancer establishment - then I encourage you to apply. If this isn't your cup of tea, then point it out to any biologist friends you might have.

2013 Summer Internships at the SENS Research Foundation

SENS Research Foundation's summer internships are for undergraduates (students working towards a Bachelor's degree) and students who have just completed their undergraduate work. Interns in this program can expect to do a considerable amount of scientific research using various techniques in the biosciences, which can include PCR, western blotting, DNA purification, gel electrophoresis, and many others. Each intern will be working on a different project, so no two will be doing the exact same thing. Though interns will build their lab skills considerably during their internship period, the strongest applicants will already have laboratory experience.

In 2013, SENS Research Foundation will be placing summer interns at four different locations: SRF's own Research Center in Mountain View, California; the Buck Institute for Research on Aging in Novato, California; the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina; and SUNY Upstate Medical University in Syracuse, New York. You will be able to apply to all four of these locations at the same time using our application. Note that the SRF Research Center and the Buck Institute are in the same metropolitan area: the San Francisco Bay Area.

The application deadline for our summer internship program is March 31, 2013 at 11:00 PM PST. However, there will be an early deadline for applicants who would like to be considered for the SUNY Upstate program: February 24th, 2013 at 11:00 PM PST. Each program will run on its own schedule, with its own stipend and arrangements.

Connections make the world go round, and certainly do wonders for your future career in a field. This is a chance to make important connections in the longevity science community, working in laboratories run by leaders in the field, and at the same time start to do your part to advance the state of rejuvenation biotechnology. You might take a look at the SENS Research Foundation's annual reports for an in-depth look at the ongoing work that takes place in their research center and partner laboratories in the US and Europe.

Source:
http://www.fightaging.org/archives/2013/02/are-you-an-ambitious-life-science-student-intern-at-the-sens-research-foundation-this-summer.php