Can Deprenyl (Selegiline) Extend Human Lifespan
I've been looking at this drug as of late for possible depression treatment as SSRI's have done nothing for me.... Good Read here
Can Deprenyl (Selegiline) Extend Human Lifespan?
by Ben Best
Several years ago L-deprenyl (selegiline) was the darling drug of life-extensionists. Some negative Parkinson's Disease studies then caused Deprenyl to fall into disrepute among both life-extensionists and conventional gerontologists. But recent studies merit a re-evaluation of deprenyl by life extensionists. And there are good reasons why the negative Parkinson's Disease studies which have discouraged gerontologists should be considered irrelevant for lifespan increase.
In 1988 Dr. Joseph Knoll -- Professor and Chairman of the Department of Pharmacology at Semmelweis University of Medicine in Budapest, Hungary -- published a paper [*1] reporting that with L-deprenyl (now often called selegiline) he more than doubled the remaining life expectancy of 24-month old rats from 36 to 50 months. A few years later, a Canadian group reported [*2] that the same dosage of deprenyl (the equivalent of 10 mg/day for a 170-pound person) used by Knoll had extended the remaining life expectancy of 24-month old rats by 16%.
The reasons for this discrepancy may be because the Canadians had used Fischer-344 rats which have a life expectancy of 28 months. Dr. Knoll in demonstrating a doubling of life spans had used Wistar-Logan rats that live 36-months. The Fischer-344 rats used by the Canadians had been within 4 months of the end of their lives.
In 1992 the Japanese researcher K.Kitani doubled the dose of deprenyl used by the previous researchers to 0.5mg/kg in a lifespan study on Fischer-344 rats beginning at 18 months and 24 months. Although average lifespan was increased 15% and 34% respectively, no increase in maximum lifespan was seen [*3]. Knoll attributed these failures to achieve his own dramatic results to the use of the short-lived Fischer rats and to the excessively high dose of deprenyl [*4]. At the 2004 American Aging Association Conference Kitani reported that he had halved the dose to the standard 0.25mg/kg/injection (3 times per week) and increased mean life span 44% for females and 32% for females starting from 24 months. Nonetheless, no significant increase in maximum lifespan was seen.
Deprenyl had been discovered in 1964 by Knoll and his associates. Currently, only the L-form (selegiline) of this drug is in widespread clinical use, primarily for its ability to inhibit the "B" form of MonoAmine Oxidase.
MonoAmine Oxidase (MAO) is an enzyme that functions in the brain to break-down (inactivate) neurotransmitters. The "A" form, MAO-A, is found in most neurons and is most effective for breaking-down the neurotransmitters serotonin, adrenalin & noradrenalin. MAO-B, by contrast, is found in non-neuron brain cells (glia cells called astrocytes) and is more effective in breaking-down the neurotransmitter dopamine.
Drugs that inhibit MAO-A are used as anti-depressants, whereas drugs that inhibit MAO-B are more effective as treatments for Parkinson's Disease. Reducing the breakdown of serotonin, adrenalin & noradrenalin with MAO-A inhibition not only reduces depression, but elevates blood pressure -- often an undesireable "side effect". Deprenyl will inhibit both MAO-A and MAO-B in dosages above 30-40 mg per day, so it was initially used as an anti-depressant at these dosages. But soon, deprenyl's selective inhibition of MAO-B at dosages below 20 mg/day made it a useful therapy for treating the chronic dopamine depletion of Parkinson's Disease -- without the blood-pressure elevation problems.
It is quite an unexpected result that a MAO-B inhibitor could double the remaining life expectancy of normal animals. But recent studies continue to affirm the ability of deprenyl to extend remaining lifespan (although not to the extent of doubling), of both laboratory animals and Alzheimer's Disease patients.
Using deprenyl dosages equivalent to 4 mg/day for a 170-pound person, middle-aged female Syrian hamsters experienced a 16% increase in maximum lifespan, but no effect was seen for males [*5]. One reason for the sexual divergence might be indicated by the fact that male Wistar rats have twice the P450 cytochrome enzyme in the liver as female Wisters.
Although it takes too many years to do lifespan studies on long-lived species, another experiment was conducted on elderly beagle dogs. The dogs were given the equivalent of 77 mg/day for a 170-pound person. 80% of the deprenyl dogs survived to the end of the experiment, whereas only 39% of the placebo dogs survived [*6].
Studies of deprenyl on Syrian hamsters and Fischer-344 rats have also demonstrated improved spatial learning and long-term memory [*7 & *8]. One study on Alzheimer's Disease patients showed a 15% improvement in behavioral symptoms with 10 mg/day deprenyl [*9]. Another study of Alzheimer's patients receiving 10 mg/day deprenyl showed an increase in median survival of 215 days as compared with placebo [*10]. A well-controlled study looking for a 20% difference on the Brief Psychiatric Rating Scale found failed to find that much difference between Alzheimer's patients and controls after 6&nbps;months on 10mg daily deprenyl [*11].
How does deprenyl extend lifespan? More pointedly, why would a substance that prevents dopamine breakdown result in extended youth? In fact, deprenyl not only inhibits MAO-A and MAO-B, but has a number of other independent actions that protect neurons (protecting the brain). It is only possible to guess, but as the ultimate regulator of hormones and the immune system the brain can exert its effect on every cell in the body. A youthful brain may be the key to a youthful body.
Part of deprenyl's protection of brain cells comes through the inhibition of MAO-B. Over 80% of the dopamine in the human brain is in the basal ganglia. MAO-B in the basal ganglia is inhibited more than 90% by 10 mg/day of deprenyl -- resulting in a 40-70% increase in dopamine. MAO-B inhibition reduces degredation of phenylethylamine even more effectively than it inhibits dopamine degredation. Phenylethylamine stimulates release of dopamine and serotonin, besides acting as a direct stimulant on dopamine receptors [*12]
The breakdown products of dopamine resulting from MAO-B degradation are hydrogen peroxide, ammonia and an aldehyde. Aldehydes are highly reactive compounds that can modify proteins. Ammonia is also toxic, particularly to glia (non-neuron brain cells). Hydrogen peroxide in the presence of ferrous iron ion can lead to hydroxyl radicals, the most toxic of all free radicals. Hydrogen peroxide can easily pass into the cell nucleus where it can encounter iron ions to produce hydroxyl radicals that damage and mutate DNA. (Carnosine, which has been shown to reduce cellular senescence, also inhibits MAO-B free radical generation.)
Besides causing MAO-B inhibition, deprenyl can increase the formation of the natural anti-oxidant. enzymes SuperOxide Dismutase (SOD) and catalase in the substantia nigra, striatum and cerebral cortex regions of the brain. Joseph Knoll has contended that it is this effect of deprenyl, rather than MAO-B inhibition, which results in lifespan extension. Most deprenyl lifespan studies have been conducted on rats, whose brains (unlike those of humans) use MAO-A, rather than MAO-B, to metabolize dopamine. So inhibition of MAO-B metabolism of dopamine seems unlikely to be the mechanism by which deprenyl extends a rat's lifespan.
The dose of deprenyl for the induction of antioxidant enzymes is highly dependent upon the strain, age, sex and species of animal. The equivalent of 75 mg/day for a 170-pound person produced optimal superoxide dismutase induction in old C57BL male mice [*13] and female beagle dogs [*14]. Female Fischer-344 rats achieve maximum induction at the equivalent of 15 mg/day for a 170-pound person. SOD & catalase activity is less for larger or smaller doses -- meaning 15 mg/day is optimal. The optimal dose for male Fischer-344 rats is ten times greater -- the equivalent of 150 mg/day for a 170-pound person. Old female Fischer-344 rats, on the other hand, do best with the equivalent of about 75 mg/day. Dosages of the equivalent of 150 mg/day significantly decrease the activity of glutathione peroxidase in both old and young female Fischer-344 rats [*15]. Without glutathione peroxidase (or enough catalase) to eliminate hydrogen peroxide, SOD conversion of superoxide to hydrogen peroxide can lead to the formation of the deadly hydroxyl radical.
The fact that both too much or too little deprenyl can reduce its anti-oxidant effect -- and the fact that optimum dose varies so greatly with strain, age, sex and species -- makes the prediction of optimal dosages for human beings on the basis of animal studies very difficult.
DNA repair capability has been positively correlated with maximum lifespan for many species and many "accelerated aging diseases" are associated with DNA repair defects. DNA damage also correlates with neurodegenerative disease. DNA repair is facilitated by the enzyme Poly(ADP-Ribose) Polymerase-1 (PARP-1) . Deprenyl has been shown to increase PARP-1 expression in hamster cells subjected to gamma-radiation, suggesting an additional possible mechanism for deprenyl in neuroprotection and lifespan extension [*16].
Whether or not deprenyl is a "wonder drug", the multiplicity of its effects are certainly a cause for wonder. In the 1990 Canadian lifespan study [*2] it was noted that the control animals had significantly higher Blood Urea Nitrogen (BUN), indicative of deprenyl's protection of the kidney. Deprenyl protects neurons from hypoxia/ischemia damage [*17]. Deprenyl increases cell levels of the natural anti-oxidant enzyme superoxide dismutase by direct alteration of gene/protein transcription/synthesis. By the same kind of direct action on DNA, deprenyl also increases nerve growth factors, proteins halting "cell suicide" (apoptosis) and other proteins involved in protecting neurons -- 40 or more such genes in all [*18].
At least two studies have shown that deprenyl could be of value in reducing ischemic damage in the brain. A study involving 14 days of deprenyl on rats [*19] and 20 minutes of hypoxia/ischemia showed reduction of area of damage of 75% in the forebrain and about 20% in the cortex. For the hippocampus, 30-38% of the area was damaged in controls, but no damage was seen in the depenyl-treated rats. A similar study on gerbils [*20] showed reduced damage to the CA1 area of the hippocampus for deprenyl given more than a week before, immediately after and more than a week after ischemia due to vessel occlusion. Cell cultures exposed to peroxynitrite have been protected from apoptotic DNA damage by deprenyl [*21].
Understanding the role of deprenyl in the treatment of Parkinson's Disease is important for life-extensionists because of the controversy surrounding the question of whether deprenyl protects neurons in a clinical setting or merely treats symptoms. A great deal of research has gone into attempting to answer this question.
Parkinson's Disease is the second most common neurodegenerative disease (after Alzheimer's Disease). It affects about 2% of the population. The neurodegeneration in this case is very selective -- it is the dopamine-producing neurons in the pars compacta of the substantia nigra ganglion that degenerates. To compensate for the loss, dopamine receptors in the striatum of the brain increase in number -- and dopamine turnover & release accelerates. But when dopamine in the striatum is depleted to 20% the original level, compensation has reached its limit and symptoms of Parkinson's Disease appear. Levodopa can be used by brain cells to synthesize dopamine, which can alleviate Parkinsonian symptoms, but the degeneration continues. Within 5-10 years from the start of treatment the effectiveness of levodopa begins to fail, while side-effects become intolerable.
There is ample evidence that the neuron degeneration in the substantia nigra is due to free-radical oxidation. Most studies indicate a 30-40% increase of iron in the substantia nigra of Parkinson patients. Aluminum -- which can displace iron bound to protein and thereby increase reactivity -- is also increased. Although Parkinson symptoms can be induced in laboratory animals by injecting iron into the substantia nigra, this does not prove that iron-accumulation is what ultimately causes Parkinson's Disease.
Reduced glutathione levels are lower in the substantia nigra in Parkinsonism, and there is evidence that this depletion occurs earlier than the increase in iron. Depletion of reduced glutathione may itself be subsequent to a prior cause. That oxidation contributes significantly to neurodegeneration may still not answer the question of what begins the whole process.
Two large clinical trials, both consisting of about 800 Parkinson patients, have served as a focus for the role of deprenyl as a neuroprotective agent in clinical practice. The first of these trials was DATATOP (Deprenyl And Tocopherol Antioxidant Therapy Of Parkinsonism), a randomized, double-blind study at 28 US and Canadian sites that tested the effectiveness of 2000 IU/day Vitamin E and 10mg/day deprenyl in delaying the need for levodopa therapy in early-stage Parkinson patients.
Vitamin E was never shown to be of any benefit in Parkinsonism. But the first released results announced that deprenyl had delayed the need for levodopa therapy by a factor of 57% [*22]. A subsequent publication of DATATOP results [*23] was less enthusiastic. It acknowledged that at least part (and perhaps all) of the delayed need for levodopa was due to deprenyl relieving symptoms (substituting for levodopa), while the underlying neurodegeneration continued. A claim was made for neuroprotection, but the study design could not prove such protection. After a few more years of patient follow-up, the conclusions ceased to be positive at all: "deprenyl does not provide an advantage in preventing or postponing complications from levodopa therapy" and "by the end of the study, subjects receiving the different treatments had comparable degrees of parkinsonian disability and were taking comparable amounts of levodopa" [*24 & *25].
The second large clinical trial, the PDRG-UK (Parkinson's Disease Research Group of the United Kingdom) contained a more devastating indictment of deprenyl: after 5-6 years follow-up, patients taking a combination of levodopa with deprenyl had a 57% greater chance of dying than patients taking levodopa alone [*26]. A storm of protest arose in the medical community [*27 & *28]. The results were counter to those found in nearly all previous studies. Pooled results from many small studies showed opposite results from those of PDRG-UK, namely slightly reduced mortality with deprenyl. The PDRG-UK trials had not been blinded at all, patients knew their medications and could change groups at will. Nearly 50% of the subjects had dropped-out completely. The most seriously afflicted patients could have been the ones most earnest about receiving both medications. The fact that deprenyl was only used in combination with levodopa opens the possibility of levodopa/deprenyl and levodopa/deprenyl/Parkinson's Disease interactions which might not be relevant to life-extensionists taking deprenyl.
Unlike other studies, PDRG-UK trial participants had not been excluded on grounds of excess age, other diseases or other medications being taken. The PDRG-UK patients receiving levodopa alone had death rates over 3 times as great, and the levodopa/deprenyl patients had death rates over 5 times as great, as the non-deprenyl and deprenyl-treated patients (respectively) in the pooled results of 7 other controlled long-term studies. In defense, A.J.Lees and other representatives of PDRG-UK wrote that these conditions more accurately reflect true clinical practice than trials that screen for participants more carefully [*29]. Lees and associates also stated that their study design was superior to that of DATATOP and several others because mortality rather than advent of levodopa therapy was chosen as the end-point. A better interpretation is probably that the PDRG-UK study was able to command authority by having so many patients, but should be regarded with suspicion because of the poor controls which allowed the study to become so large.
Although causes of death due to deprenyl had not been well identified in the PDRG-UK paper, a subsequent paper co-authored by A.J.Lees concluded that "Therapy with deprenyl and levodopa in combination may be associated with severe orthostatic hypotension not attributable to levodopa alone" [*30]. A more carefully designed study, which studied deprenyl alone, rather than in combination with levodopa, seemed to confirm a side-effect of orthostatic hypotension for Parkinson patients taking deprenyl [*31]. But the DATATOP study had reported "No significant treatment-related changes in blood pressure or pulse recordings" although a 2% incidence of non-life-threatening cardiac arrhythmias were reported for the deprenyl group [*23].
Two subsequent (smaller) clinical trials attempted to address the design flaws of DATATOP and PDRG-UK, both being double-blind, placebo-controlled. One used mortality as the end-point [*32] and the other used measures of physical disability [*33]. Both concluded that deprenyl has neuroprotective action in clinical use. In support of this conclusion is another study which found more neurons and fewer neuron inclusion-bodies in the substantia nigra of autopsied patients who had been taking deprenyl [*34].
Even if 10 mg/day deprenyl does lower blood pressure for some Parkinsonian patients, it is questionable how relevant this result is for people without neurodegenerative disease who are taking deprenyl in smaller doses for life-extension or cognitive-preservation purposes. Transient elevated blood pressure is more often encountered in such cases, which is why morning dosing is common. And it should not be forgotten that Parkinsonian patients have already lost over 80% of their substantia nigra neurons -- with the remaining neurons typically being in a degenerative state. Moreover, Parkinson's Disease also attacks other midbrain nuclei, including the locus coeruleus (which produces most of the brain's norepinephrine). With norepinephrine (and serotonin) at about 50% of normal levels, it is understandable that Parkinsonian patients might suffer from low blood pressure.
Life-extensionists have understandably had a difficult time trying to determine what dose would be optimal for a human seeking the life-extension and neuroprotective benefits of deprenyl. Dosages in excess of 20-30 mg/day could create high blood pressure problems by MAO-A inhibition. Dosages in the 10 mg/day range would reduce the oxidation stress of the breakdown products of dopamine metabolized by MAO-B, but the resulting elevated dopamine levels might not be desirable. Deprenyl binds to MAO-B irreversibly, and it takes 2 weeks for MAO-B levels to return to normal. A single 5 mg dose can cause 86% MAO-B inhibition within 2-4 hours. Inhibition remains at 90% for 5 days, and does not return to baseline for 2 weeks [*35]. Deprenyl induction of enzyme synthesis (including, presumably, anti-oxidant enzymes) can take place at levels below those required for MAO-B inhibition [*21].
Therefore, a dose in the range of 1 mg/day might be optimal for a 40-year-old 170-pound person. Twice-weekly dosing has been based on the fact that deprenyl binds MAO-B irreversibly. But more frequent dosing might be better for steady induction of enzyme synthesis.
Aside from body weight, age is a very important consideration. As a person gets older, neurons decrease in number while glial cells (which synthesize MAO-B) increase -- meaning that MAO-B levels increase with age. This may be the reason that dopamine content of the striatum (caudate nucleus) typically decreases by 13% per decade after age 45. A person over 45 would want to counteract the excessive MAO-B in a dose proportional to his or her age. This could mean up to 5 mg daily for an elderly person with no symptoms of Parkinson's Disease or Alzheimer's Disease. Deprenyl has been shown to produce vasodilation by rapid increase in nitric oxide production and to protect the vascular endothelium from the toxic effects of amyloid-beta peptide.
Whether or not deprenyl can extend maximum lifespan, there is reason to believe that it can extend mean lifespan and protect from neurodegenerative disease. There may be considerable individual variation in what dose is optimal. Decisions based on incomplete information are never very satisfying, but such decisions are -- and will always be -- a condition of life.
[*1] "Longevity Study with (-)Deprenyl" Joseph Knoll
MECHANISMS OF AGING AND DEVELOPMENT 46:237-262 (1988)
[*2] "Maintenance on L-Deprenyl Prolongs Life in Aged
Male Rats" Milgram, et.al.
LIFE SCIENCES 47:415-420 (1990)
[*3] "Chronic Treatment of (-)Deprenyl Prolongs the Life
Span of Male Fischer 344 Rats" K.Kitani, et.al.
LIFE SCIENCES 52:281-288 (1992)
[*4] "Sexually Low Performing Male Rats Die Earlier Than Their High
Performing Peers and (-)Deprenyl Treatment Eliminates This
Difference" Joseph Knoll
LIFE SCIENCES 54:1047-1057 (1994)
[*5] "Chronic Treatment of Syrian Hamsters with Low-Dose Selegiline
Increases Life Span in Females But Not Males" S.Stoll, et.al.
NEUROBIOLOGY OF AGING 18:205-211 (1997)
[*6] "Treatment with L-Deprenyl Prolongs Life in Elderly Dogs"
W.W. Ruehl, et.al.
LIFE SCIENCES 61:1037-1044 (1997)
[*7] "Age-Related Memory Decline and Longevity under Treatment
with Selegiline" S.Stoll, et.al.
LIFE SCIENCES 25/26:2155-2163 (1994)
[*8] "Long-Term Treatment of Male F344 Rats with Deprenyl"
NEUROBIOLOGY OF AGING 18:309-318 (1997)
[*9] "Selegiline in Treatment of Behavioral and Cognitive Symptoms
of Alzheimer Disease" S.Tolbert & M.Fuller
THE ANNALS OF PHARMACOTHERAPY 30:1122-1129 (1996)
[*10] "A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both
as Treatment for Alzheimer's Disease" Mary Sano, et.al.
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[*11] "L-deprenyl in Alzheimer's Disease" M. Freedman, et.al.
as Treatment for Alzheimer's Disease" Mary Sano, et.al.
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[*12] "2-Phenylethylamine: A Modulator of Catecholamine Transmission
in the Mammalian Nervous System?" I.A.Paterson, et.al.
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[*13] "(-)Deprenyl Increases Activities of SuperOxide Dismutase and
Catalase in certain Brain Regions in Old Male Mice"
M-C. Carrillo, et.al.
LIFE SCIENCES 54:975-981 (1994)
[*14] "(-)Deprenyl Increases Activities of SuperOxide Dismutase (SOD)
in Striatum of Dog Brain" M-C. Carrillo, et.al.
LIFE SCIENCES 54:1483-1489 (1994)
[*15] "(-)Deprenyl Increases Activities of SuperOxide Dismutase and
Catalase in Striatum but not Hippocampus" M-C. Carrillo, et.al.
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[*16] "L-Selegiline Potentiates the Cellular Poly(ADP-Ribosyl)ation
Response to Ionizing Radiation" C.Brabeck, et.al.
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[*17] "Selegiline treatment after transient global ischemia in gerbils
enhances the survival of CA1 pyramidal cells in the hippocampus"
BRAIN RESEARCH 757:260-267 (1997)
[*18] "(-)-Deprenyl Reduces PC12 Cell Apoptosis by Inducing New
Protein Synthesis" W.G.Tatton, et.al.
JOURNAL OF NEUROCHEMISTRY 63:1572-1575 (1994)
[*19] "L-Deprenyl Reduces Brain Damage in Parts Exposed to Transient
Hypoxia-Ischemia" S. Kollema,et.al.
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[*20] "The neuroprotective effect of (-) deprenyl in the gerbil
hippocampus following transient global ischemia J.Kulunonen, et.al
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[*21] "Neuroprotection by (-)-deprenyl and related compounds"
Wakako Maruyama & Makoto Naio
MECHANISMS OF AGING AND DEVELOPMENT 111:189-200 (1999)
[*22] "Effect of Deprenyl on the Progression of Disability in Early
Parkinson's Disease" The Parkinson Study Group
NEW ENGLAND JOURNAL OF MEDICINE 321:1364-1371 (1989)
[*23] "Effect of Tocopherol and Deprenyl on the Progression of
Disability in Early Parkinson's Disease" The Parkinson Study Group
NEW ENGLAND JOURNAL OF MEDICINE 328:176-183 (1993)
[*24] "Impact of Deprenyl and Tocopherol Treatment on Parkinson's
Disease in DATATOP Subjects Not Requiring Levodopa"
The Parkinson Study Group
ANNALS OF NEUROLOGY 39:29-36 (1996)
[*25] "Impact of Deprenyl and Tocopherol Treatment on Parkinson's
Disease in DATATOP Subjects Requiring Levodopa"
The Parkinson Study Group
ANNALS OF NEUROLOGY 39:37-45 (1996)
[*26] "Comparison of therapeutic effects and mortality data
of levodopa and levodopa combined with selegiline in patients
with early, mild Parkinson's disease" A.J.Lees, et.al.
BRITISH MEDICAL JOURNAL 311:1602-1607 (1995)
BRITISH MEDICAL JOURNAL 312:702-705 (1996)
[*28] "Selegiline and Mortality in Parkinson's Disease"
ANNALS OF NEUROLOGY 40:841-845 (1996)
[*29] "Selegiline and Mortality in Parkinson's Disease: Another View"
ANNALS OF NEUROLOGY 41:282-283 (1997)
[*30] "Autonomic effects of selegiline: possible cardiovascular
toxicity in Parkinson's disease" A.Churchyard, et.al.
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[*35] "Clinical Pharmacokinetics and Pharmacodynamics of Selegiline"
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"Pharmacological actions of l-deprenyl (selegiline) and other
selective monoamine oxidase B inhibitors" M.Youdim & J.Finberg
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"Extension of Life Span of Rats by Long-Term (-)Deprenyl
Treatment" Joseph Knoll
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"(-)Deprenyl can Induce Soluble SuperOxide Dismutase in
Rat Striata" A.Clow, et.al.
JOURNAL OF NEURAL TRANSMISSION 86:77-80 (1991)
"Increased CNTF Gene Expression in Process-Bearing Astrocytes
Following Injury Is Augmented by R(-)-Deprenyl" N.A.Seniuk,et.al.
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"Oxidative Stress and AntiOxidant Therapy in Parkinson's Disease"
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NEURODEGENERATION AND NEUROPROTECTION IN PARKINSON'S DISEASE
C.Warren Olanow, et.al., Editors (1996)
"Attempts to obtain neuroprotection in Parkinson's disease"
NEUROLOGY 49 (Suppl 1):S26-S33 (1997)
"Selegiline and Neuroprotection in Parkinson's Disease"
C.W.Olanow & P.Riederer, Editors
NEUROLOGY 47 (Suppl 3) December 1996