Deprenyl -- extending the life of dogs?

Life Sci. 1997;61(11):1037-44. 

Treatment with L-deprenyl prolongs life in elderly dogs.Ruehl WW, Entriken TL, Muggenburg BA, Bruyette DS, Griffith WC, Hahn FF.

Deprenyl Animal Health, Overland Park, KS 66210, USA.

Eighty two beagle dogs ranging in age from 2.8 to 16.4 years and in weight from 6.3 to 15.8 kg were allotted to 41 pairs and administered placebo or 1 mg/kg L-deprenyl orally once daily for 2 years and 10 weeks. When survivorship for all dogs in the study was analyzed there was no significant difference between the L-deprenyl and placebo treated groups, most likely due to the (expected) survival of virtually all young dogs in both groups for the duration of the study. To assess whether L-deprenyl treatment begun in later life might enhance canine longevity in a fashion similar to that documented in rodents we also examined survival in a subset of elderly dogs who were between the ages of 10 and 15 yrs at the start of tablet administration and who received tablets for at least 6 months. In this subset, dogs in the L-deprenyl group survived longer (p < 0.05) than dogs in the placebo group. Twelve of 15 (80%) dogs in the L-deprenyl group survived to the conclusion of the study, in contrast to only 7 of 18 (39%) of the dogs who received placebo (P=0.017). Furthermore, by the time the first L-deprenyl treated dog died on day 427, 5 placebo treated dogs had already succumbed, the first on day 295. Specifically with respect to dogs, the findings reported herein suggest daily oral administration of 1 mg/kg L-deprenyl prolongs life when begun in relatively healthy dogs 10-15 years of age and maintained for the duration of the individual's life, but in any event for no less than six months.

PMID: 9307048 [PubMed - indexed for MEDLINE]

J Pharmacol Exp Ther. 2006 Apr;317(1):387-94. Epub 2005 Dec 13.

Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [®-(-)-deprenyl].Yasar S, Justinova Z, Lee SH, Stefanski R, Goldberg SR, Tanda G.

Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. syasar@jhmi.edu

l-Deprenyl [selegiline, ®-(-)-deprenyl] is a selective inhibitor of monoamine oxidase B (MAO-B) used in the treatment of Parkinson's disease and proposed as an antidepressant and an aid for cigarette-smoking cessation and treatment of psychostimulant abuse. Beneficial therapeutic effects of ®-(-)-deprenyl may also result from indirect actions. Brain levels of dopamine and beta-phenylethylamine (beta-PEA), a behaviorally active endogenous trace amine, increase after ®-(-)-deprenyl treatment due to MAO-B blockade and ®-(-)-deprenyl is metabolized to ®-(-)-methamphetamine and ®-(-)-amphetamine, suggesting that ®-(-)-deprenyl may have psychostimulant-like behavioral effects. Indeed, ®-(-)-deprenyl produces psychostimulant-like discriminative-stimulus effects in experimental animals. Here, we tested the hypothesis that psychostimulant-like behavioral effects of ®-(-)-deprenyl are mainly mediated by its metabolites. Male Fisher F344 rats were trained to discriminate i.p. injection of 1.0 mg/kg (S)-(+)-methamphetamine or 10.0 mg/kg cocaine from injection of saline using two-lever choice schedules of food delivery or stimulus shock termination. When ®-(-)-deprenyl was tested by substitution, it had (S)-(+)-methamphetamine- and cocaine-like discriminative-stimulus effects, but only at doses of 10 to 30 mg/kg, doses 10 to 20 times higher than those selective for MAO-B inhibition. Ro 16-6491 [N-(2-aminoethyl)-4-chlorobenzamide hydrochloride], a selective inhibitor of MAO-B enzyme activity without psychoactive metabolites, had no psychostimulant-like discriminative effects. In addition, blockade of ®-(-)-deprenyl's metabolism with SKF 525A (beta-DEAE-diphenylpropylacetate hydrochloride; 50 mg/kg i.p.) reduced or eliminated ®-(-)-deprenyl's psychostimulant-like discriminative effects. When beta-PEA synthesis was blocked by NSD 1015 (m-hydroxy-benzyl-hydrazine; 30 mg/kg i.p.), there was a modest reversal of ®-(-)-deprenyl's psychostimulant-like discriminative effects under some conditions, indicating a facilitatory modulation of the psychostimulant-like discriminative effects of ®-(-)-deprenyl metabolites by elevated levels of beta-PEA under certain conditions.

PMID: 16352699 [PubMed - indexed for MEDLINE]

I don't think the first study posted here would pass a peer review. The name of the group that conducted the research is "Deprenyl Animal Health" -- leading me to believe they are pretty biased...

Previous posts on deprenyl and lifespan:

The question is whether it's a good thing to increase SOD. Antioxidant enzymes are NEGATIVELY correlated with species max LS (1,2); expressing extra SOD without extra CAT  could actually INCREASE free radical stress by converting minimally-toxic superoxide into more-toxic hydrogen peroxide without the capacity to break it further down to water; SOD knockouts fail to show accelerated mortality except under artificially-indduced high oxidative stress; Down's syndrome is characterized by high SOD activity; etc.

"Superoxide dismutase mimetics [EUK-134 or EUK-8] elevate superoxide dismutase activity in vivo but do not retard aging in the nematode Caenorhabditis elegans" despite the fact that they protect against hihg-level oxidative stress and prevent brain damage after a stroke or induced seizure (3).

Most notably, "Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice" (4), despite the fact that increased SOD in this model also leads to increased CAT.

Deprenyl is often cited as a counterexample, but it really isn't.  Yes, Knoll made an exciting single report (and repeated it in several journals), but he's the ONLY person to report an extension of max LS: lots of others show increases in av'g bu t not max, no extension at all, or even *increased* mortality. Flat ad hominem: Knoll had the patent on the stuff.  See the desperate attempts to reconcile the data between different studies on pp. 3-8, esp. the lifespan discussions on pp 7-8, of (1). Much of this info (but without, alas, the unpublished stuff sumarized in (1)) is put in a tabular form in (2), which makes the fundamental lack of anything like a logical pattern in the results clear. IMO, this shows pretty clearly that even if you believe there's something to it as a life-extension drug, there is just no way that one can rationally USE it as such at this time as there is no basis upon which to reasonably extrapolate a dose which can be expected to consistently extend even AV'G LS in humans.

There are no trials in normal, healthy humans, & the studies in both early and late PD are in sum quite inconclusive on the safety of deprenyl. See:

http://groups.google.....4A@aimnet.com
http://groups.google.....BC@aimnet.com
http://groups.google.....84@aimnet.com

http://bmj.com/cgi/c...ll/317/7153/252
http://bmj.com/cgi/c...l/316/7139/1191
http://groups.google...m&output=gplain

(The first 3 largely go over the same ground, albeit from slightly
different angles; the others cover newer material).

A recent editorial comment on the study from which the last post is
abstracted:

http://www.neurology...s/55/12/1785#29

"Laboratory studies suggest that selegiline has properties that
theoretically could confer neuroprotection; however, evidence for this
in clinical trials is unfortunately lacking. ... Prescribing
medications such as selegiline on faith, with little evidence-based
efficacy, ignores the negative side of this practice, including
unnecessary expense to the patient, and the potential of deleterious
drug interations. (ref. 14)." The comment seems especially relevant in
the present discussion.

It doesn't appear to give any reliable benefits in animal systems; it seems to kill the folks it's designed to TREAT; I just do not see how the risk:benefit calculation can be fudged to make it come out in favor of use by young, healthy people.

-Michael

1. Kitani K, Minami C, Isobe K, Maehara K, Kanai S, Ivy GO, Carrillo MC.
Why (--)deprenyl prolongs survivals of experimental animals: increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects.
Mech Ageing Dev. 2002 Apr 30;123(8):1087-100. Review.
PMID: 12044958 [PubMed - indexed for MEDLINE]

2. Kitani K, Kanai S, Ivy GO, Carrillo MC.
Assessing the effects of deprenyl on longevity and antioxidant defenses in
different animal models.
Ann N Y Acad Sci. 1998 Nov 20;854:291-306. Review.
PMID: 9928438 [PubMed - indexed for MEDLINE]

3. Keaney M, Matthijssens F, Sharpe M, Vanfleteren J, Gems D.
Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but
do not retard aging in the nematode Caenorhabditis elegans.
Free Radic Biol Med. 2004 Jul 15;37(2):239-50.
PMID: 15203195 [PubMed - indexed for MEDLINE]

4. Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ.
Ubiquitous overexpression of CuZn superoxide dismutase does not extend life
span in mice.
J Gerontol A Biol Sci Med Sci. 2000 Jan;55(1):B5-9.
PMID: 10719757 [PubMed - indexed for MEDLINE]

Comments?

Lex the Wonder Dog, Ronald Klatz's pet and mascot of A4M,
was on 5 mg deprenyl every two days. Note that he was also
on PBN.

http://www.worldheal...p/133,1125.html

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I think it's just plain sketchy to take too many "life extension" compounds in desperate hope that the exceptionally weak evidence will just magically work for me.

The current body of evidence available suggests that the safest way to live a long and healthy life are:

a) Excercise and eat a healthy diet (this can include supplements to make up for extra oxidative stress etc.)
b) Do CR (this can include supplements to compensate for what you miss out on with CR)

I think it's just plain sketchy to take too many "life extension" compounds in desperate hope that the exceptionally weak evidence will just magically work for me. 

The current body of evidence available suggests that the safest way to live a long and healthy life are:

a)  Excercise and eat a healthy diet (this can include supplements to make up for extra oxidative stress etc.)
b)  Do CR (this can include supplements to compensate for what you miss out on with CR)

I'd say that's a fairly accurate assesment.

As a reminder re:life extension supplements, I'd say MR is probably the most knowledgeable guy in the world (and not yet desperate so it would affect his judgement, which I think might be the case for example with Paul Wakfer and the likes), I would recommend everyone to check out his views on the matter:

http://www.imminst.o...=238&t=11396&s=

Be sure to check out the embedded links too, especially the ones in the first few paragraphs.

Re: what to expect from strategy a), MR has made some good estimates there too

http://www.imminst.o...60

Strategy b) is more of a black box. MR has argued in [1] that the proportionality principle (roughly getting as much extended life as you the level of restriction) holds to humans too humans, however, I talked to Aubrey de Grey (to whom MR works for or something) personally at Transvision 2006 Conference in Helsinki and he said (as I recall it):

""While Michael's paper was almost as good an argument for human CR as you can possibly make (much better than I expected), I think there were some subtle issues in reasoning and data interpretation that make me pretty much remain in my earlier position that CR probablydelivers only few additional years on top of otherwise healthy life-style [as outlined in [2]]. Really it mostly comes down on how you interpret the data, which is at this point basically a judgement call. All and all, I don't question the health benefits of CR but I just would not expect too much from life extension viewpoint at least at this point. Also, I have a sneaking suspicion that people who CAN actually stay on CR are the ones that are least likely get benefits because of their unique metabolism."

We did not get into details why he remained in his original position, I asked whether he was going to publish counter response, and he
said he might just do that if he finds the time. I don't know about everyone else, but I'd be happy to settle even with some preliminary
comments from Aubrey regarding this issue.

I really hope Aubrey does not get angry for me quoting him publicly, as I did not clear this with him beforehand. I just thought other
people should know this too, as many have high regard for his opinion (well, at least I do).

1. Rae MJ.
You don't need a weatherman: famines, evolution, and intervention into aging.
AGE. 2006 May 23;[Epub ahead of print]
No PMID assigned yet.
http://dx.doi.org/10...1357-006-9002-z

2: de Grey AD.
The unfortunate influence of the weather on the rate of aging: why human caloric restriction or its emulation may only extend life expectancy by 2-3 years.
Gerontology. 2005 Mar-Apr;51(2):73-82. Review.
PMID: 15711074 [PubMed - indexed for MEDLINE]
http://www.sens.org/weatherPP.pdf

Edited by opales, 24 August 2006 - 09:39 AM.

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If you note A4M's link above, Lex was not on CR,
but they managed to push him to the equivalent
human age of 115. He would likely have lasted way past
120 had they not decided to put him to sleep after his
leg handicap caused by the stroke.

The items on his regimen which were probably significant
in extending his lifespan were PBN, deprenyl, DHEA,
melatonin and the aloe vera extract, Acemannan.