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[A1CR]

[posted on behalf of CRON4healthyfurure]

Natural enzyme destroys lipofuscin; No need to go grave robbing, de GREY!

Fortunately, real scientists have nullified de Grey's ramblings.

If one were convinced that lipofuscin mediates aging, then finding ways to overexpress endogenous cathespin f would qualify as "anti-aging". This circumvents the risky alternative of incorporating exogenous genes and enzymes into cells, advocated by some.

So, either overexpress cathepsin f, or, figure out how it is regulated and manipulate that. Small-molecular weight compounds that could influence gene transcription could yield a quick and dirty pharmacologic approach, or, longer-term, gene vectors that introduce extra copies could be utilized.

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http://mcb.asm.org/cgi/content/abstract/26/6/2309

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"Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, mice deficient in cat F were generated via homologous recombination. Although cat F(-/-) mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. cat F was found to be expressed throughout the central nervous system (CNS). cat F(-/-) neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age."

[MR]

CRON4healthyfuture wrote:

> Fortunately, real scientists have nullified de Grey's ramblings.

Fortunately, real scientists have endorsed, presented at scientific
meetings on, and cosigned a paper on, these particular ramblings (2). Or
are Jay Jerome, Ana Maria Cuervo, and Bruce Rittmann (et al) not "real
scientists" either?

> If one were convinced that lipofuscin mediates aging, then finding ways to overexpress endogenous cathespin f would qualify as "anti-aging".

Maybe; that would be metabolic speculation, of course. The study that
you cite (1) shows only that NORMALIZING levels of this enzyme in
animals engineered to LACK it also normalizes the resulting neuronal
lipofuscinosis and late-onset neurological disease; this is as you'd
expect, as the enzyme in question metabolizes PRECURSORS of lipofuscin
in the lysosome (it does not "destroy lipofuscin," contrary to your
subject line). However, it does not show that INCREASING the normal
level in healthy (but aging) organisms further decreases lipofuscin
accumulation below the normal rate of its formation in such organisms.

Also, even if it did do this, the cas would not be proven that it was a
net benefit. Just because X is bad for you, doesn't mean that a *given*
anti-X intervention will on lead to an overall improvement in your healht.

Animals with knockouts for p53 get more cancer and die faster than
normal, healthy organisms; animals with EXTRA p53 get less cancer, but
despite this either age and die more quickly due to stem cell exhaustion
(5) or die at a normal rate from as-yet-unclear causes (6).

Cf the case of hypercholesterolemia: it's clearly the major risk factor
for CHD, and yet most lipid-lowering drugs (fibrates (fenofibrate
[Lipidil], clofibrate [Atromid-S], gemfibrozil [Lopid]) and resins
(colestipol [Colestid], cholestyramine [Questran]) increase total
mortality rates in hypercholesterolemic patients. And of course, no one
to my knowledge holds that lipofuscin ALONE mediates aging. Messing with
metabolism is always side-effect-prone.

> This circumvents the risky alternative of incorporating exogenous genes and enzymes into cells, advocated by some.

Even if this intervention were actually effective in normal organisms
(again, unproven by this experiment), worked systemically as opposed to
only in the nervous system (not necessarily implied by this experiment),
and was without side effects (again, unlikely in a classic
metabolism-wrench intervention) it would not constitute a replacement
for the intervention to which you refer (introducing soil enzymes, via
injection and/or gene therapy, to destroy existing lipofuscin deposits
in the lysosome -- the xenohydrolase arm of the SENS project for
age-arresting/reversing biomedicine (2-4)). Contrary to your subject
line, this enzyme does NOT destroy lipofuscin; it destroys metabolic
wastes which, when not broken down, contribute to the FORMATION of
lipofuscin. Thus, this intervention would slow down the accumulation of
lipofuscin to some extent, but could not destroy EXISTING lipofuscin
deposits.

In fact, as I've posted in previous discussions with you (CRON4healthyfuture) of
the xenohydrolase project, similar interventioins (upregulating or
supplementing levels of endogenous enzymes that metabolize such
precursors) have in fact been shown to reduce disease in animal models
of atherosclerosis (7) and normalization of neurodegenerative changes in
synapse structure associated with Alzheimer's disease (8,9). This is
exciting work, and points at the potential for the xenohydrolase
project, but it also illustrates my point about boosting endogenous
enzymes: (7) clearly shows that lysosomal lipase supplementation does
reduce disease with only early-stage atherosclerotic lesions, but only
slows it down in animals with advanced lesions.

An intervention that could actually destroy lipofuscin itself would be
predicted to effect the *elimination* or *reversal*, of existing,
full-blown disease.

Moreover, you seem to be assuming that the use of "exogenous" (by which
you apparently mean *foreign* , since you're here advocating precisely
the use of exogenous enzymes or genes:

> So, either overexpress cathepsin f, or, figure out how it is regulated and manipulate that. Small-molecular weight compounds that could influence gene transcription could yield a quick and dirty pharmacologic approach, or, longer-term, gene vectors that introduce extra copies could be utilized.

... as I was saying, you seem to be assuming that the use f foreign
enzymes is inherently risky. In fact, however, experience with humans
given enzymes that are both exogenous and foreign (to them) in the case
of recognized, congenital lysosomal storage diseases is in fact thus far
well-tolerated.(10)

By contrast, wrenching finely-balanced metabolic networks out of their
normal homeostasis usually has negative side-effects: cathepsin f is
presumably regulated at the observed level for a reason, and while it
may be a simlem matter of resource allocation tradeoff, it could well be
that excessive levels are harmful to normal metabolism. This is (again)
one of the advantages of SENS interventions as a class: they would leave
metabolism to do its normal dirty work, but then clean up the ensuing
damage -- initially at pathological levels, and later (after initial
rejuvenation) before it accumulates to such levels.

-MR

1: Tang CH, Lee JW, Galvez MG, Robillard L, Mole SE, Chapman HA.
Murine cathepsin f deficiency causes neuronal lipofuscinosis and
late-onset neurological disease.
Mol Cell Biol. 2006 Mar;26(6):2309-16.
PMID: 16508006 [PubMed - in process]
http://mcb.asm.org/cgi/content/abstract/26/6/2309
>
> =-=-=-=-=-=--=
>
> "Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, mice deficient in cat F were generated via homologous recombination. Although cat F(-/-) mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. cat F was found to be expressed throughout the central nervous system (CNS). cat F(-/-) neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age."
>
2. de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL,
Nixon RA, Rittmann BE, Sparrow JR.
Medical bioremediation: prospects for the application of microbial
catabolic diversity to aging and several major age-related diseases.
Ageing Res Rev. 2005 Aug;4(3):315-38. Review.
PMID: 16040282 [PubMed - indexed for MEDLINE]


3: de Grey AD.
Bioremediation meets biomedicine: therapeutic translation of microbial
catabolism to the lysosome.
Trends Biotechnol. 2002 Nov;20(11):452-5.
PMID: 12413818 [PubMed - indexed for MEDLINE]

4. de Grey AD.
Appropriating microbial catabolism: A proposal to treat and prevent
neurodegeneration.
Neurobiol Aging. 2006 Apr;27(4):589-95. Epub 2005 Oct 3.
PMID: 16207503 [PubMed - in process]

5. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann
H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty
G, Bradley A, Donehower LA. p53 mutant mice that display early
ageing-associated phenotypes. Nature. 2002 Jan 3;415(6867):45-53. PMID:
11780111

6. EMBO J 2002 Nov 15;21(22):6225-6235 Links 'Super p53' mice exhibit
enhanced DNA damage response, are tumor resistant and age normally.
Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P,
Flores JM, Weill JC, Blasco MA, Serrano M. PMID: 12426394

7. Du H, Schiavi S, Wan N, Levine M, Witte DP, Grabowski GA.
Reduction of atherosclerotic plaques by lysosomal acid lipase
supplementation.
Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):147-54. Epub 2003 Nov 13.
PMID: 14615393 [PubMed - indexed for MEDLINE]

8. Butler D, Brown QB, Chin DJ, Batey L, Karim S, Mutneja MS, Karanian
DA, Bahr BA.
Cellular responses to protein accumulation involve autophagy and
lysosomal enzyme activation.
Rejuvenation Res. 2005 Winter;8(4):227-37.
PMID: 16313222 [PubMed - indexed for MEDLINE]

9: Bendiske J, Bahr BA.
Lysosomal activation is a compensatory response against protein
accumulation and associated synaptopathogenesis--an approach for slowing
Alzheimer disease?
J Neuropathol Exp Neurol. 2003 May;62(5):451-63.
PMID: 12769185 [PubMed - indexed for MEDLINE]

10. Brooks DA, Kakavanos R, Hopwood JJ.
Significance of immune response to enzyme-replacement therapy for
patients with
a lysosomal storage disorder.
Trends Mol Med. 2003 Oct;9(10):450-3. Review.
PMID: 14557058 [PubMed - indexed for MEDLINE]