One of the ways in which normal metabolic processes degrade important components in your body (such as kidneys, heart, skin and blood vessels) is through the generation of advanced glycation endproducts (AGEs). Your body needs certain proteins in order to work properly; the creation of AGEs involves taking two or more of these proteins and sticking them together with chemical gunk, preventing them from doing their jobs. This is known as crosslinking; day in and day out, it is taking place in your body. Some AGEs are short-lived but common, growing or declining in population in response to your diet and metabolic peculiarities. Others are very long-lived or impossible for the body to break down; they build up over the years, and eventually there's enough of this gunk to seriously damage you.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

Fortunately, there are classes of chemical compound - drugs, in other words - that could break up the AGEs that are leading you part of the way towards age-related disease and eventual death. Predictably, they are known as AGE-breakers, and a number of companies have been involved in research and development in this field in the past five to ten years. Amongst them is Alteon, whose staff are presently attempting to gain regulatory approval of alagebrium (or ALT-711) based upon very promising animal studies and (unfortunately) not so promising human studies. I devoted a post to the company not so long ago.

Alteon has gone through many of the reshapings common to young pharmaceutical development companies; the latest would seem to place them more in line for financial viability - and thus continuing development of ALT-711 for modest goals relating to the treatment of specific conditions. This is the sort of profile that maximizes the chance of attracting funding and clearing sufficient regulatory hurdles to make it to profitability.

...

One might view Alteon and the development of ALT-711 as something of a transition from the old to the new in the community of folk seeking to extend the healthy human life span. It has its roots in the old school drug development pipeline and firm focus on supplements and things you can put in a pill. The aims, however, are well within the Strategies for Engineered Negligible Senescence (SENS), in that Alteon's founders and employees seek to effectively and deliberately repair a small portion of the cellular damage that cause age-related degeneration.

There are many, many different types of AGEs, and researchers have no exhaustive catalogue of them all; any given AGE-breaker is going to tackle one subset at most. Alagebrium most likely attacks a type of AGE much more common in old animals than old humans, for example - which is why it works so much better for rats than us. Biotechnology has come a long way since alagebrium was first proposed and engineered, however, and a good thing too; scientists now have a much better grasp on which AGEs are most common, and thus must be broken to best help aged or diabetic humans. A compound called glucosepane is presently at the top of the list.

In the extracellular matrix of the skin of a non-diabetic 90-year-old glucosepane accounts for about 50 times the protein cross-linking as all other forms of protein cross-linking.

Legendary Pharmaceuticals is one small company chasing down an AGE-breaker for glucosepane; you might recall that founder John D. Furber gave a presentation at the SENS2 conference on the subject. From their website:

Other damage affects extracellular proteins throughout the body, such as collagen and elastin. Recycling of these proteins proceeds slowly; they are out of reach of proteasomes and lysomes. Over time, they are chemically altered by reactive chemicals and sugars, which form covalent adducts and crosslinks. Crosslinked and glycated extracellular proteins contribute to many pathologies of aging and diabetes, including atherosclerosis, heart disease, stiffness, kidney diseases, arthritis, and erectile dysfunction. We are studying several promising mechanisms for breaking these crosslinks, as well as drugs which quench reactive free-radicals before they can chemically damage the proteins.

I should note that the company website also has a rather good resource page for glycation and crosslinking of proteins if you'd like to learn more about the chemistry and consequences for your health:

Glycation changes the shape and properties of proteins. Crosslinking reduces the flexibility, elasticity, and functionality of the proteins. Furthermore, the chemical modifications of glycation and crosslinking can initiate harmful inflammatory and autoimmune responses. "AGE and nonenzymatic crosslinks are demonstrated to signal inflammatory cytokines, extracellular matrix expansion, angiogenesis, and growth factors." [deGroof] Glycation has been found in connective tissue collagen, arterial collagen, kidney glomerular basement membrane, eye lens crystallins, nerve myelin proteins and in the circulating low-density lipoprotein (LDL) of the blood. [Bucala]

Over on the other side of the world, a fair-sized Indian company called Torrent Pharmaceuticals has been working on AGE-breakers for a while:

Of the 7 research projects currently in pipeline, 3 are focussed on Diabetes. The first of them is Torrent Pharma's patented Advanced Glycosylation End-products (AGE) breaker compound, which has great potential for the treatment of diabetes related vascular and cardiac complications. This proprietary molecule has the promise of a block-buster in the offing.

You'll have to do more digging on the Torrent website and related sources if you want to find out what it is, how it performed in animal tests, and how soon in might be heading to trials and the marketplace. I leave that as an exercise for the interested reader.

The bottom line: there is an opportunity to greatly affect the aging process here, using the huge, existing drug development and marketing infrastructure - if the right compounds can be identified and constructed in a cost-effective fashion. Modern biotechnology is becoming ever better at doing just that, and funds are presently invested in the task - albeit not as much as we'd all like.

I expect the largest hurdles to a glucosepane AGE-breaker in the next 10 years to be regulatory, just as they are for every other aspect of medicine these days. Isn't it nice to live in a society in which so much effort is devoted to ensuring you won't live to see healthy life extension technologies?

Technorati tags: biotechnology, life extension, medical research

Posted by Reason at October 13, 2006 6:51 PM | TrackBack (10)