08.30.08

Vote to Help Gain Amex Funds For Longevity Research

Posted in Uncategorized at 9:44 am by heaven

There are three days left - until September 1st - in which to vote and comment on the submitted Amex Members Projects to determine the top 25 that will move on to the next stage. The combination of votes and public interest will ultimately determine how American Express awards $2.5 million in philanthropic funding. From the website:

We're inviting you to come together to share ideas for projects that could make a difference in the world. Then it's up to you to support, and ultimately vote on, which projects get $2.5 million in funding from American Express.

As you no doubt know, the Methuselah Foundation volunteers have a well-formed longevity science proposal in the running:

Create a program that utilizes college undergraduates to perform research in a variety of scientific venues surrounding fighting age related diseases such as Alzheimer’s, Parkinson’s, Heart Disease and Cancer and overall extension of healthy human life. Hiring researchers is exceedingly expensive. By outsourcing projects to undergraduate students, laboratory use and labor costs are negligible, and the students receive college credit for their work.

...

People who believe that one day they will peacefully die in their sleep are living in ignorance. The vast majority of age related deaths are a slow, painful, and degrading process over many years of later life. Watching my beloved grandmother die as a result of an age related disease and seeing our adored family friend fall prey to cancer has inspired me to learn more about death and aging pathology, and more importantly, to do something about it.

This is a well-planned project, sized to the funds available. With the backing of the Methuselah Foundation, already very involved in organizing undergraduate and graduate research volunteers, it would do well if victorious. As the vote counts ramp up in the final days of selecting the top 25 projects, it's up to us to help keep longevity science in the spotlight. It is by far the most discussed project, but it needs more votes. Tell your friends!

You don't have to be an Amex cardholder, but you do have to be a US resident in order to register and vote. Some instructions via the Methuselah Foundation blog:

1. Go to this website: http://www.membersproject.com/

2.a. If you are not an Amex Card Member: Click on "Guest Members Log In" in the upper right corner of the screen. Then click on "Guest Members Sign Up Here" at the bottom of the next screen.

2.b. If you are an Amex Card Member: Click on "Cardmembers Log In" on the right side of the screen. If you don't already have an online login click on "Create a Log In" in the next screen.

3. Complete the Registration Form which will give you your Login ID.

4. Once you are logged in on the home page, you can either a) Enter 'Undergrads Fighting Age Related Disease' in the Search box or b) click on 'Health' then 'Diseases and Disorders' at the bottom right of the home page, and scroll down to 'Undergrads Fighting Age Related Disease'. Alternately, here is a direct link to the project page:

http://www.membersproject.com/project/view/BVVE2C

5. Click on the project and then click on the 'Nominate this Project' button. Then click on 'Post Your Comments' at the bottom of the screen to have your say, as discussion board activity counts towards the nomination of the top 25 projects.

Opportunities to take a few minutes to step in and help secure funds for research don't come along every day for most of us. Take advantage here and know that you made a difference!

Rejuvenation Research for August 2008

Posted in Uncategorized at 9:44 am by heaven

The latest issue of Rejuvenation Research (volume 11, number 4) is available online. As usual, the contributions come from a broad range of fields in the life sciences applicable to extending healthy life span and repairing the damage of aging. Here are a couple of examples that focus on the nuts and bolts of pushing aging cells to perform greater feats of regeneration:

Aging, Stem Cells, and Mammalian Target of Rapamycin: A Prospect of Pharmacologic Rejuvenation of Aging Stem Cells

What is the relationship between stem cell aging and organismal aging? Does stem cell aging cause organismal aging or vice versa? Will stem cell aging aggravate age-related diseases? And what is stem cell aging?

As suggested herein, hyperstimulation of signal transduction pathways can render cells compensatorily irresponsive. And the hallmark of stem cell aging is poor responsiveness to activating stimuli. On the basis of the hypothesis that insensitivity to stimuli is in part due to hyperactivation of the target of rapamycin (TOR), this article suggests a means of pharmacologic rejuvenation of stem cells and wound-healing cells.

This is a useful way of looking at the issue of aging stem cells. I'm not sold on the specific details - the focus on TOR - but the general strategy of exploration and experimentation with stem cell response sounds good. If the cells are still good to go, a great deal of good might be accomplished with some comparatively simple targeted manipulations.

By way of an aside, you might recall that TOR is associated with the biomechanisms of calorie restriction, but then it's one of the pathways associated with everything of importance in the realm of metabolism.

Host Cell Mobilization for In Situ Tissue Regeneration

The goal of the present study was to investigate whether host biologic resources and environmental conditions could be used for in situ tissue regeneration, which may eliminate the need for donor cell procurement and subsequent in vitro cell manipulation. To address this aim, we implanted a common biomaterial into mice and characterized the infiltrating cells to determine their regenerative potential.

...

the infiltrating cells are capable of differentiating into multiple cell lineages, including osteogenic, myogenic, adipogenic, and endothelial lineages, if appropriate conditions are provided. These results suggest that it is possible to recruit a predominance of cells with multilineage potential into a biomaterial scaffold. Therefore, it may be possible to enrich the infiltrate with such cell types and control their fate, provided the proper substrate-mediated signaling can be imparted into the scaffold for in situ tissue regeneration.

Which is a rather long-winded way of saying that suitably designed nanostructures and control over stem cell signaling should be able to replace first generation cell delivery therapies in many situations. In theory, medical science could move the apparatus of programming and activating stem cells entirely inside the body - no need to pull cells out for culturing and manipulation or find transplant sources. It's a promising vision.

08.28.08

Views From the “Change Metabolism to Slow Aging” Camp

Posted in Uncategorized at 9:43 am by heaven

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

This true in a way: extension of healthy life will be a long time coming if metabolic manipulation is the only path taken by the research community. Fortunately, metabolic re-engineering is not the only way ahead. It's not the most efficient way ahead either. The better path is to refrain from changing the way in which our metabolic processes work. Instead we should indentify the biochemical differences between an old, damaged metabolism and a young, healthy metabolism - and then repair them, thus reversing aging.

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective that slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

All that said, I noticed that Pure Pedantry is commenting today on an analysis by researchers Jan Vijg and Judith Campisi. It's a view from the metabolic re-engineering camp, dug in for the long, slow haul:

All in all, this a very good review that I recommend reading in its entirety. They strike a note of cautious optimism that I think is right on: we are learning more about this field but there is no justification for irrational exuberance.

Not on that path, in any case. It's hard to be hugely overwhelmed by progress that might, maybe, do a little good for young people fifty years from now. What is needed today is a determined effort to do good for the aged people of twenty to thirty years from now.

Filling in the Gaps Between Telomeres and Mitochondria in Aging

Posted in Uncategorized at 9:43 am by heaven

You might recall that it was back in 2007 I first mentioned research into links between age-related changes in mitochondria, the power plants of the cell, and telomeres, the structures at the end of your chromosomes that form a counter for cell state. Your cell is a complex, unified machine, so in many ways its not surprising to find links between portions of the clockwork that are known to be important in aging. You should wander back into the archives and refresh your memory:

Linking Telomere Shortening and Mitochondrial Damage?

We know that mitochondrial damage is tied to aging via mechanisms such as the production of damaging free radicals such as [reactive oxygen species] - and that some researchers are working on solutions, such as the ability to replace all mitochondrial DNA in the body via protofection. We also know that progessive telomere shortening is tied to aging and age-related disease, and a number of different groups are working on strategies to safely lengthen telomeres.

There is strong evidence to believe that "tied to aging" in this context means "contributes to aging as a cause." Remember that aging is no more than an accumulation of damage in biochemical systems; when we look at these changes that take place with aging, we are looking at damage. This paper offers the possibility that if we repair or prevent the progressive accumulation of mitochondrial degeneration and damage, then the telomeres will take care of themselves - if the results are replicated, of course.

More On Telomere Shortening and Mitochondrial Dysfunction

So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.

As I said back then, this cries out for more research - which seems to be taking place. A recent paper pulls the antioxidant catalase into the mix:

Telomerase deficiency promotes oxidative stress by reducing catalase activity:

We used cultured mouse embryonic fibroblasts (MEF) isolated from mice lacking telomerase activity (Terc(-/-)) to analyze the redox balance and the functional consequences promoted by telomerase deficiency.

...

6-month-old Terc(-/-) [mice] showed higher oxidant capacity, lower catalase activity, greater oxidative damage, and higher TGF-beta1 and fibronectin levels ... In summary, telomerase deficiency reduces catalase activity, determining a redox imbalance that promotes overexpression of TGF-beta1 and extracellular matrix proteins.

Back a few years, researchers demonstrated that pouring extra catalase onto the mitochondria - via a genetic mutation to target the chemical to where it was needed - extends healthy life span. Catalase soaks up some fraction of damaging free radicals before they can degrade the mitochondria that produce them, and slowing mitochondrial damage is very beneficial to health and longevity. Is catalase level the mechanism by which telomerase helps out the mitochondria? Stay tuned: the more we know, the easier it will be to develop repair technologies that can set things back to the way they were when we were young.

08.26.08

The Aging Immune System, Thymic Involution, and Wnt4

Posted in Uncategorized at 9:42 am by heaven

As you might recall, one reason that the immune system declines with age relates to its capacity of cell types. An aged immune system is clogged with useless memory cells, leaving few resources for capable cells to fight new threats. The other reason is the decline of the thymus, source of immune cells:

The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells. Coupled with a similar, though less dramatic age-linked decline in bone marrow function, this translates to a reduction in immune responsiveness

But what if we could regenerate the thymus, restoring it to a vigorous production of new immune cells? That could be one way of pushing out the limits, and making the accumulation of memory cells less harmful at any given age. One of the long-time Fight Aging! readers kindly pointed me to a recent article at Scientist Live on this topic:

Successfully combating illness in elderly individuals can potentially add years to a life. At the centre of this struggle lies an immune system that becomes compromised with age, subsequently leaving the body susceptible to diseases younger bodies would normally keep at bay.

Dr. Claude Perreault and a team of Canadian and Finnish scientists has identified a protein able to stimulate the production of T-cells, the white blood cells involved in the recognition and the elimination of infectious agents.

...

why does the thymus involute early in life so that it leaves older people immunodeficient. For example, thymic atrophy begins as early as one year of age. Progressive thymic involution is responsible for the fact that elderly individuals have very poor thymic function. They produce very little T-Lymphocytes and because of that they are more susceptible to infections, cancer, and autoimmune disease.

We also found that one major characteristic of the thymus found nowhere else in [the] lymphoid organs is the expression of a protein called Wnt4. We hypothesised that Wnt4 had a role in T-Lymphocyte development and that by providing high levels of Wnt4 to hematopoietic progenitor cells we would enhance [production of immune cells]. That is how it began.

We did two series of experiments. In the first set, we induced over-expression of Wnt4 in hematopoietic stem cells and found that compared to mice that received standard cells those that received cells producing high levels of Wnt4 had a bigger thymus and produced 3-4 times more T-Lymphocytes. ... when we knocked out Wnt4 there was thymic atrophy.

Overall, these studies suggest that Wnt4 is necessary for normal T-cell production and that over-expression of Wnt4 is sufficient to improve [production of immune cells]. In the future, we hope to evaluate the best way to give Wnt4 to animals or humans in order to find whether this molecule can be used to treat thymic involution.

An interesting start; I suspect we'll hear more along these lines in the years ahead.

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