IUBio Biosequences .. Software .. Molbio soft .. Network News .. FTP

Are AGEs and Lipofuscin related? Could ALT-711 eliminate lipofuscin?

ufotruth at ix.netcom.com ufotruth at ix.netcom.com
Wed Jan 6 16:38:01 EST 1999

>Lipofuscin hasn't been discussed here for a long time, and it may be
>much more important to aging than has traditionally been thought, so
>I'll do a bit more than answer your questions.

Thank you. I really appreciate that you are willing to do more than
just answer my questions. :-)

>The definition you quote is adequate (except that the pigmentation
>of age spots/liver spots is not normally classed as lipofuscin,
>and I doubt that it's chemically similar), but it omits the cell

Well, what interested me about the definition is that I have read on
many different websites that age/liver spots are caused by an
accumilation of Advanced Glycation End-Products and their resulting
Crosslinks. Then I read that definition that age/liver spots are
caused by lipofuscin, so it made me start wondering if they were
related to each other, or possibly, a variation of the same thing.

You see if they are basically the same thing, then ALT-711 might not
be just an AGE/Crosslink breaker, but also a lipofoscin

>types which accumulate the highest levels of lipofuscin, namely the
>pigmented epithelium of the retina.  There is a consensus that the
>levels reached in those cells does indeed interfere with cellular
>metabolism, leading to blindness from macular degeneration.  The
>reason these cells suffer so severely is that they are responsible
>for destroying the worn-out light-sensitive material in the other
>cells in the retina, and that wearing-out happens at a phenomenal
>rate: a given unit of photoreceptor lasts only a week or so.

Thanks. I appreciate the information. It seems to me that any waste or
junk that accumilates in a cell during the aging process would have to
cause problems, at least to "some" degree, and cannot be beneficial.

>The effect in other cells, however, is in great doubt: most people
>reckon that the accumulation of lipofuscin is completely harmless
>at the levels seen elsewhere, even by very old age.  Thus, it's the
>usual situation -- a completely uncontroversial "theory of eventual
>aging" which by no means translates into a theory of actual aging.

Well, perhaps the truth of the matter is that MANY different things
only harm cells a "little", even when a person is very old, but when
all the different aspects of aging are combined it is enough to cause
MAJOR harm and even death.

Also, perhaps all the theories of "eventual aging", that have at least
some merit, could be put together and accumilated into one theory of
"immediate aging". 

One interesting thing to note is that in my opinion telomere
shortening "might", from what I have read, be the cause of most of
these various theories of "eventual aging" that altogether cause
"immediate aging".

>However, a few years ago Ulf Brunk suggested (Mutat Res 275:395-403)
>a way in which a quite low level of lipofuscin may impose stress on
>its host cells: in essence, by "distracting" the cellular recycling
>machinery, wearing out the hydrolytic enzymes that constantly (and
>vitally) break down old proteins, old mitochondria, old everything
>into their biologically elementary constituents (such as free amino
>acids) for re-use to make new cellular components.  This is still a

That is very interesting. If that is correct, and if ALT-711 could
break apart the lipofuscin, then perhaps it will be an even MORE
therapeutic drug that we already believe. 

>viable hypothesis; the cells (excluding the retina) which accumulate
>the most lipofuscin are postmitotic ones, which as you know are the
>ones that show the greatest deterioration with aging, and moreover
>the postmitotic cells that accumulate most are the ones that suffer
>most (eg motor neurons lose functionality much more badly than muscle
>fibres, as shown by cross-age transplantations (see eg Carlson et al,
>Am J Physiol 256:C1262-6)).  The only strong evidence against it is
>that vitamin E supplementation has been shown to slow accumulation
>of lipofuscin quite substantially in mice, but not to increase their
>maximum lifespan (Blackett and Hall, Age Ageing 10:191-5); that is
>potentially rather persuasive, but it needs to be repeated more
>exhaustively (on a larger scale, studying more cell types, etc).

Did it increase their average life span?

>So to your questions.  The cross-linking in lipofuscin is generally
>described as due to oxidation reactions, but AGE-like links may very
>well also be present.  If so, then an AGE breaker like ALT-711 may
>break it apart somewhat; moreover, there's nothing to say that an
>AGE breaker may not also break apart some types of oxidative cross-
>links.  There are pretty good in vitro assays for this: it's easy to

If ALT-711 can break it apart then it seems to me that Alteon might
have an even more amazing drug that we currently believe. If ALT-711
cannot break lipofuscin apart, then I hope that someone discovers one
that can.

>make lipofuscin accumulate really fast in culture, and to measure
>whether the introduction of a given chemical retards or reverses
>that accumulation.  One chemical, centrophenoxine, has long been
>touted to have this effect (Nandy and Bourne, Nature 210:313-4),
>but more recent work is less encouraging, finding some retardation
>but no definite reversal (though I again feel that we need more data
>before we can reach solid conclusions).  I would be very surprised
>if Alteon aren't doing such experiments.

Hmm. I am going to email Alteon and ask them about that. Perhaps they
will respond and give me some information.

Thanks VERY much for the response to my post. I really appreciate it
and hope that you have a great day.

Live Long and Prosper,

>Aubrey de Grey

More information about the Ageing mailing list

Send comments to us at biosci-help [At] net.bio.net