7 replies to this topic

[golddragon]

Aubrey has suggested using chemicals eg ALT-711 to break crosslinks, but are there other feasable/better options, eg

Would it be realistic to vaccinate against crosslinks (ie just completely destroy cross-linked proteins, and then prevent their buildup instead of trying to rescue them with ALT-711, etc). If we could develop antibodies against these structures a staged regular treatment should be safe and reverse changes...

David

[ag24]

I'm not sure that's a viable option Dave, because the structures that accumulate these crosslinks are the really long-lived ones with essentially no capacity for regeneratiion, like the lens of the eye and the walls of the major arteries.

Personally I think the small-molecule approach can probably be pushed a lot further than it has so far. There is a decidedly unhealthy reluctance among glycation experts in academia to work on it, but the most abundant such crosslinks have the key requirements of being (a) structurally unlike any physiological molecule, hence likely to be cleavable by drugs that are otherwise essentially harmless, and (b) rather unstable (in particular, acid-labile) so not necessarily refractory for thermodynamic reasons. (Some of the best-known links, such as pentosidine, are extremely stable (which is why they were found first, by methods involving acid hydrolysis) but they're much less abundant than glucosepane for example, and probably also than alpha-dicarbonyl links which are the ones ALT-711 is supposed to cleave.)

[olaf.larsson]

Well I think you would get a total body inflamation, a feature which is already caraceristic for the aging process. The thing I wonder is how can ALT-711 not deglycosylate glycoproteins which are supposed be glycosylated to function properly.

[Mark Hamalainen]

antibodies against these structures

I believe this happens naturally in the form of age-dependent autoimmunity, in which case it is most undesirable. It may play role in arthritis.

[ag24]

Wolfram - that's what I meant by the structural dissimilarity. The chemical linkage that links sugars onto proteins on purpose is different from the spontaneous ones that we want to break. I expect a good deal of detail will be provided by Howard Haimes at SENS2.

Osiris - right, in essence - and actually this is one potential beneficial side-effect of WILT, because autoimmunity is basically a loss of precision of the immune system's selectivity and may be partly caused by old naive T and B cells misbehaving. It's also probably partly caused by the shrinkage ("involution") of the thymus, which various people are working to fix (see eg Marilyn Thoman who will be speaking at SENS2)

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[olaf.larsson]

Osiris - right, in essence - and actually this is one potential beneficial side-effect of WILT, because autoimmunity is basically a loss of precision of the immune system's selectivity and may be partly caused by old naive T and B cells misbehaving.

I dont see it as that the immune system "missbehaves", since unnormal glycosylated protein structures appear with age it is natural för the immune system to act against them.

[Mark Hamalainen]

Thats a question of semantics. When you're young the thymus is capable of performing negative selection for all of the self-antigens the immune system could come across. As you age damages accumulate which are often specific to different tissues, and which the thymus is not equiped to simulate, therefore it is no longer capable of presenting all self-antigens for negative selection (If you consider the damage to be self, thats more semantics). Atrophy of the thymus coupled with transfer of negative selection to the peripheral immune system can partially compensate for this and so is somewhat beneficial to an aging organism. However, atrophy of the thymus is also associated with negative effects of immunosenescence.

Aging of immune cells will cause them to misbehave for the usual reasons as well (genomic instability, cancer), and as de Grey says, WILT can prevent cells from getting old enough to misbehave.

[olaf.larsson]

OK we have come to the conslusion that the age related inflamation is due to two processes:

1. Formation of abnormal proteins which serve as antigens.

2. Immune system dysregulation.

Any one of the above would be sufficient, but in real life both contribute to age related inflamation.