Pages

April 09, 2008

Life extension Update, metabolic pathway drug modification and SENS

In an Esquire magazine interview Andre Dillin, Salk Institute, indicated that they have a compound which is very effective at treating Alzheimers effects and extending life. So far that work has been on C elegan worms

But more than the apparent result, what excites and interests Dillin is the way the drug achieves its result. A-Beta does its damage by causing cell proteins to misfold; Dillin suspects that the drug works not by specifically blocking A-Beta but rather by encouraging proteins to keep folding accurately and precisely. That is, he thinks the drug works by promoting an overall cellular well-being, otherwise known as youthfulness. Specifically, he thinks the drug works by "upregulating the PHA-4 pathway," which has been defined as a pathway regulating longevity. But he thinks it does more than that. He thinks it will enable him to define and deal experimentally with youthfulness.


The article mentions doubling lifespans to 250 years. However, to achieve that effect would require more than calorie restriction effects. It would also not apply to people who are already middle age or older if it is reducing metabolic aging in half.

Andrew Dillin's research papers

The SENS and MPrize funding combined are over $11 million

SENS is looking to launch several new research projects.

AmyloSENS: Extracellular junk is aggregates of stuff that do not have any function and should ideally have been cleared out of the body, but have proven resistant to destruction. Most of this junk is termed “amyloid” of one variety or another. You may have heard of one form of amyloid – Abeta, the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else’s.

Elan Pharmaceuticals’ most recent candidate Alzheimer vaccine, bapineuzumab, has been the subject of recent excitement after the company launched a full-scale (“Phase III”) clinical trial at an unusually early point, leading to speculation that the as-yet-undisclosed preliminary results of its earlier trials may be exceptionally promising.

The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine – similar to that developed by Elan for Alzheimer’s disease – to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.

ApoptoSENS

There are three main classes of cells that sometimes acquire a metabolic state that is damaging to their neighbours. (Visceral fat cells, Senescent cells, Immune cells)

There are two main alternatives:

1. Inject something that makes the unwanted cells commit suicide but doesn't touch other cells.
2. Stimulate the immune system to kill the target cells.

Glycosens

The Methuselah Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2008.

Oncosens

We don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer. The one that I favour (and which was the topic of the third SENS roundtable, a meeting I convened in Cambridge in 2002) is called WILT, for Whole-body Interdiction of Lengthening of Telomeres.

The Methuselah Foundation is planning to launch three projects in the OncoSENS strand during 2008.

The first project aims to characterise the enzyme responsible for ALT, which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.

The second project addresses a potential problem with the WILT strategy. It’s possible that telomerase activity per se – independent of telomere length – may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called “stem cell niche”. We are arranging a project to address this question, in the blood of mice, with the world’s leading professor in the area.

Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime – protagonistic pleiotropy – is not yet widely accepted. We are therefore initiating a rigorous study into the effects of such mutations in mouse brains.

Replenisens

Cell depletion is the loss of cells without equivalent replacement. Cell depletion can be fixed in two main ways: by stimulating the division of existing cells, or by directly introducing new ones. There is a lot of active work with Stem cells, so the Methuselah Foundation does not currently intend to allocate its limited resources to projects in this area.

2 comments:

Jonathan said...

I am not sure that I agree with Aubrey on his WILT idea. I am definitely not an expert in these fields, but I do read a little. It seems like the WILT approach is pretty extreme. Don't you think that in the next 20 years, we will have enough weapons in our arsenals to take care of most types of cancer? This would negate the need for WILT, right?

bw said...

WILT is extreme but if the replenishment of new cells can be made to work then it would be workable. Other advances (like some new devices that might get us to 100% early detection by finding any cancer cell in the blood) and GIFT for boosting the immune system could greatly reduce the need for WILT and reduce deaths from cancer.

the question is if the other methods are 90-99% effective and WILT plus replenishment is 100% effective, then if you are shooting for 1000 years and not 250 years then WILT might be the better option.

Plus synthetically reversing WILT could even be possible.