04.07.09

Large Scale Analysis of Gene Expression Changes in Aging

Posted in Uncategorized at 1:00 am by heaven

Over at Ouroboros, you'll find a look at what emerges from a very large comparative analysis of gene expression changes with aging. By finding the most important differences, and tracing back to the biological mechanisms associated with these genes, we should learn something about the validity of various theories of aging, and the importance of various potential strategies for slowing or reversing aging.

The core of the thing:

We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age.

We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed.

If you've been reading Fight Aging! for a while, you'll have seen most of these processes and systems mentioned in connection to the damage of aging. The failing immune system, the role of chronic inflammation, the biochemical junk cluttering the lysosome, mitochondrial DNA damage, senescent cells, and so forth.

As they point out at Ouroboros:

While this approach will likely fail to identify those genes that are age-regulated only in a single tissue, the advantage is that those genes that do come out of this analysis are likely to be the really interesting ones - components of a common aging program that operates in multiple tissues.

CPHPC and Amyloidosis

Posted in Uncategorized at 1:00 am by heaven

Centenarians get to be centenarians by surviving or not suffering the diseases that kill everyone else. So what kills centenarians? This isn't an academic question, as we'd like to engineer a future in which none of us suffer the major diseases of aging, and all of us make it past a century in good health. Understanding the processes that slay those who survive everything else the failing body can throw at us is just as essential to the future of longevity medicine as curing cancer and repairing mitochondria.

If forced to make an educated guess today, I'd have to say that the best evidence is for amyloidosis to be the killer of the oldest old - a buildup of metabolic byproducts that eventually clogs the body's systems to the point of failure. The Supercentenarian Research Foundation outlines some of the case for that conclusion:

Coles argues [that supercentenarians] aren't perishing from the typical scourges of old age, such as cancer, heart disease, stroke, and Alzheimer's Disease. What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

Folk from the Biogerontology Research Foundation (formed "to support the application of our knowledge of the mechanisms of ageing to the relief of disability, suffering and disease in old age") were kind enough to direct my attention today to a recent update from the amyloidosis research community:

Prof Pepys’s persistence pays off

Amyloidosis is caused by the build up of abnormal "amyloid" proteins in body tissues. Prof Pepys has long believed that the key to understanding the disease is a related blood protein called SAP, which sticks to amyloid fibres and stops enzymes removing them.

The FT has covered his work several times. My predecessor David Fishlock described in 1990 Prof Pepys’s discovery of a way to image SAP and amyloid fibres. I wrote in 1995 and 2002 about progress in developing a drug called CPHPC, which aimed to clear the destructive amyloid deposits from patients by removing the protective SAP from their blood.

Prof Pepys was working then in collaboration with Roche. But the Swiss pharmaceutical giant eventually pulled out.

"While we had promising early results [with CPHPC] they were not enough to benefit patients with advanced disease," he says. "Something more dramatic is needed."

That something turns out to a combination of CPHPC with an antibody - a molecular guidance system designed to seek out amyloid deposits in vital organs.

Now Prof Pepys has reached an agreement with another big pharmaceutical group, UK-based GlaxoSmithKline, to collaborate on producing a treatment for amyloidosis based on the CPHPC-antibody combination.

Those of us interested in progress towards the tools needed to remove or repair changes in our tissues that accumulate with age should follow amyloidosis research with interest. Some fraction of the degenerations of aging is caused by just this sort of buildup of unwanted chemical aggregates. Strategies under development for dealing with specific aggregates may turn out be more broadly applicable to future engineered longevity therapies.

Convincing the Body to Clear its Own Biochemical Waste

Posted in Uncategorized at 1:00 am by heaven

A fraction of the damage of aging is caused by the build-up of biochemical waste within and between our cells. Some is common to all of us and a byproduct of the normal operation of metabolism, such as the amyloid implicated in Alzheimer's, which can be found in small amounts even in the young, or lipofuscin that increasingly harms our lysosomes. Other types of biochemical waste are peculiar to those unfortunate enought to suffer particular forms of genetic damage - such as the mutation that causes Huntington's disease.

It is instructive to watch early research and progress in treating diseases where the damage done depends upon a build up of unwanted proteins. Some of the lessons learned and new technologies deployed could be turned to address other types of biochemical, ones whose buildup contributes to the aging process. Here's an example of what I mean:

A new study has identified a potential strategy for removing the abnormal protein that causes Huntington's disease (HD) from brain cells, which could slow the progression of the devastating neurological disorder. [Research describe] how an alteration to the mutated form of the huntingtin protein appears to accelerate its breakdown and removal through normal cellular processes.

...

A key observation was that [the method used], while increasing the removal of mutant huntingtin, had little effect on the normal version of the protein. "One of the major challenges of research into neurodegenerative disorders like Huntington's, Alzheimer's and Parkinson's diseases - all of which involve accumulation of proteins within the brain - has been how to activate degradation machinery that only removes the disease-causing proteins and leaves normal proteins untouched."

As the ability of researchers to manipulate the elements of human biochemistry grows, we should expect to see ever more opportunties to harness and redirect existing cellular capabilities as a part of a new therapy.

All of What Was, Some of What Is, and None of What Will Be

Posted in Uncategorized at 1:00 am by heaven

The mind of humanity dwells somewhat in the now, a great deal in the recent past, and very little in the future. The greatest attention is focused on what is and what recently was - an outcome of our evolutionary history. You can imagine how a focus on learning to live in the world of the the recent past was a predictor for success under most circumstances for our more primitive ancestors.

These days, stand still to ruminate upon recent events and you're liable to have a building erected above you while you pause, and fifteen new technologies dropped into your lap to boot. The evolved biases stand, however: while a great many people claim to look foward with wisdom and sagacity, few do more than transpose the fundament and structure of last week ahead by seven days. We humans just don't put much effort into thinking about how the future will in fact be different from the past, and what that means for our actions and choices.

One manifestation of this bias is seen in the nature of the periodic articles about centenarians that are a staple of the popular press. Now that researchers can start to talk about biochemistry and genes in relation to longevity, these pieces are cropping up in the popular science press too. The underlying question is always "how did they do it, living to 100 like that?" More accurately, the question beneath that is "how can I do it too?"

The standard form of the answers to this question is always rooted in the recent past. If things never changed, if medical technology and culture remained static, how could I do as well as a centenarian? But of course all that stasis is implicit, hidden under the covers, as it is in so many other considerations of the future. The world of last week never ends in the inner mind of humanity, and we shall dwell in it forever.

Here's a short Scientific American piece in which S. Jay Olshansky says some sensible things about centenarian health and longevity as an example of the type.

SciAm: Is it possible that Dosova gave birth to a daughter when she was 54 years old? Olshansky: Believe it or not, that's exactly what you would think for someone who has had a very long life. In centenarians and supercentenarians - people over 110 - you see a higher level of fecundity much later in life. These women will still be having periods and producing eggs later than the average female. As long as the body believes it is reproductively active and keeps producing certain sex hormones, these seem to help protect the body against aging. As soon as menopause occurs, things begin to change in a woman's body very rapidly. If you look at records of centenarians, many of them in fact had children in their late 40s. So if Dosova did have a child at the age of 54, it would likely corroborate her story rather than detract from it.

Here, the claim of a 130 year old woman is fairly safe to throw out without iron-clad documentation. That she's a centenarian seems sound, but 130 stretches plausibility. The commentary on longevity is still sound, however.

But back to your future. In the world of last week, in which nothing really changes but your age, you won't make it to 100. That's a safe bet no matter how well you take care of your health. The only thing that will enable many of us to live in good health past a century of life is the advance of medical technology - in other words, new science and new therapies that don't exist in the here and now.

The speed with which medicine advances is predicated upon just how many of us support that advance. If you live your life in the land of last week, or the land of how your parents lived, or any of the other seductive places that your evolved nature causes you to be predisposed to enjoy, then I'm sorry to say that you're not helping. The coming decades could see some of the most transformative advances in medical technology yet, and it is possible to envisage with some precision the tools and therapies that could rejuvenate the old by repairing the damage of aging. This will only happen rapidly enough to help those of us reading this now if many more people get behind the wheel and push.

Recognize that the greatest determinant of your future health and longevity is medical science and technology that has yet to be developed, not whatever was a good health practice last week. Then figure out how you can help.

Redesigned and Spreading Out in Middle Age

Posted in Uncategorized at 1:00 am by heaven

As you might have noticed, I've implemented a minor redesign here at Fight Aging! and over at the Longevity Meme in the past couple of days. It's a sort of spreading out in middle age: as the average size of monitors grows, an layout designed for 800x600 pixel screens begins to look cramped and low-rent. Now we're on a layout that has 1024x768 in mind, and, by the magic of adding a lot of empty space, the same old material suddenly looks much more up to date and sophisticated. Funny the way that works.

A couple of other odds and ends were tided up as I notice them, and I hope to achieve more of the same in the next few days. The search function here at Fight Aging! now uses Google rather than the increasingly hopeless in-built Movable Type search, for example, and is as a result much more useful. I've moved it up in the left navigation to a position that reflects its newly acquired utility.

So while my attention is focused on these and similar housekeeping matters, it's a good time for you, the audience, to point out things that might need updating or are otherwise not up to scratch. I'm hoping that nothing was outright broken by the update, but it's always possible I missed an item stuck away in the corners, or that appearances are suffering in one of the less common browsers. Let me know if that's the case.

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