DEPRENYL- EXTENDING LIFESPAN
By James South
MA
Deprenyl is a drug that was discovered around 1964-65 by Dr. Joseph Knoll and
colleagues. It was originally developed as a “psychic energizer,” designed
to integrate some amphetamine-like brain effects with antidepressant effects.
(1) Also known as L-deprenyl, (-)-deprenyl, and selegiline, deprenyl (DPR)
has been intensively researched over the past 36 years – many hundreds of
research papers on DPR have been published. Knoll has stated that DPR
“…is an exceptionally lucky modification of PEA [phenylethylamine], an
endogenous … member of the family to which also the transmitters noradrenaline
and dopamine belong.” (13) [See diagram.] DPR has shown a unique and
exciting pharmacologic/clinical profile. It is the only potent, selective
MAO-B inhibitor in medical use. (1) DPR is a “catecholamine activity enhancer.”
(2) DPR has been shown to protect nerve cells against a wide (and growing)
number of neurotoxins. (3,4) DPR has also been shown to be a “neuroprotection/
neurorescue agent” when nerve cells are exposed to damaging or stressful
conditions. (5)
DPR has become a standard treatment for Parkinson’s disease. (6) DPR is also
useful in treating drug-resistant depression. (8,9) In aged rats, DPR has
proven to be a highly effective “sexual rejuvenator.” (10) DPR also shows
promise as a cognitive enhancement agent. (10) DPR has also proven in four
different rat studies and one dog study to be an effective life-extension agent,
even increasing the “technical lifespan” in Knoll’s rat experiments.
(11,12) and these are just some of DPR’s reported benefits.
DEPRENYL: MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that DPR was a unique kind of MAO inhibitor – a
selective MAO-B inhibitor, without the “cheese effect.” To fully
appreciate what this means, some technical background is necessary.
Some of the most important neurotransmitters in the brain are the monoamine
(MA) transmitters: serotonin, dopamine and noradrenalin. After being
secreted into the synaptic gap, where one neuron connects to another, many to
the transmitter molecules are reabsorbed by the secreting neuron and then
disposed of by enzymes called “monoamine oxidases” (MAO). This prevents
excessive levels of transmitters from accumulating in the synaptic gap and
“over-amping” the brain. However, with aging MAO activity significantly
increases in the human brain, often to the point of severely depressing
necessary levels of MA transmitters. (1) In the 1950s the first
antidepressant drugs to be developed were MAO inhibitors (MAOI). By the
1960s however, MAOIs began to drop out of medical use due to a
dangerous side-effect – the so-called “cheese effect.” When most MÅOIs are used
in people consuming a diet rich in a substance called “tyramine,” a dangerous,
even fatal, high blood pressure crisis can be triggered. Tyramine is found in
many foods, including aged cheeses, some wines, beans, yeast products, chicken
liver and pickled herring, to name just a few. (23)
By 1968, further research had shown that there were two types of MAO-A and
B. It is primarily intestinal MAO-A that digests incoming tyramine. Most
of the MAOIs that have been used clinically inhibit both MAO-A and MAO-B, thus
setting up the danger of the cheese effect by inhibiting intestinal and brain
MAO-A, allowing “toxic” tyramine levels to accumulate. DPR is unique
among clinically used MAO-Is. At normally used clinical dosages (10-15
mg/day), DPR is a selective MAO-B inhibitor, so it doesn’t prevent intestinal
MAO-A from digesting dietary tyramine.(1) In addition, DPR has the unique
ability to prevent tyramine from getting into noradrenalin-using nerve calls,
and it’s only when tyramine enters noradrenalin nerve cells that control
arterial blood pressure that it triggers the “cheese effect.” (1) DPR thus
has a dual “safety lock” in preventing the “cheese effect,” making it far safer
than other MAOIs. At doses over 20-30 mg/day, however, DPR does start to
significantly inhibit MAO-A , so there is some risk of the “cheese effect” at
these higher (rarely clinically used) doses. (1)
MAO-A enzymes break down serotonin (5-HT) and noradrenalin (NA), and to a
lesser extent dopamine (DA). MAO-B breaks down DA and the “traceamine”
phenylethylamine (PEA). At doses of 5-10 mg per day DPR will inhibit MAO-B about
90%. (1) It was initially presumed that DPR would increase synaptic levels of DA
in DA-using neurons, and this lead to its use to treat Parkinson’s disease in
the late 1970s, Alzheimer’s disease in the 1980s-90s, and depression starting in
the late 1970s. In his 1983 paper on the history of DPR’s clinical benefits to
its unique MAO-B effects. (1)
Yet many experts have questioned whether DPR’s MAO-B inhibition can
significantly increase synaptic DA levels. (14,15) This is due to the fact
that MAO-B is found only in glial cells in the human brain, non-nerve cells that
support, surround and feed the brain’s billions of neurons. (1) And whether
there is any exchange of DA between these glial cells and the DA-using neurons
is still an unanswered question. It is commonly believed that it is MAO-A
in DA neurons that breaks DA down. By the 1990s Knoll believed he had discovered
the “real basis” of DPR’s being a MAO-B inhibitor. (2)
Yet as will be made clear shortly, even if DPR’s originally
hypothesized mode of action – directly increasing synaptic DA levels through
MAO-B inhibition – is false, DPR’s MAO-B inhibition still provides part of its
benefit.
DEPRENYL: CATECHOLAMINE ACTIVITY ENHANCER
During the 1990s Knoll’s DPR research took a new direction. Working with rat
brain stems, rabbit pulmonary and ear arteries, frog hearts and rats in shuttle
boxes, Knoll discovered a new mode of action of DPR that he believes explains
its widespread clinical utility. (2,16) Knoll discovered that DPR (and its
“cousin”, PEA) are “catecholamine activity enhancers” (CAE).
“Catecholamines” (CA) refers to the inter-related neurotransmitters dopamine
(DA), noradrenalin (NA) and adrenalin. CAs are the transmitters for key
activating brain circuits – the mesolimbic-cortical circuit (MLC) and the locus
coeruleus (LC). The neurons of the MLC and LC project from the brain stem,
through the mid-brain, to the cerebral cortex. They help to maintain focus,
concentration, alertness and effortful attention. (17) DA is also the
transmitter for a brainstem circuit – the nigrostriatal tract – which connects
the substantia nigra and the striatum, a nerve tract that helps control bodily
movement and which partially dies off and malfunctions in Parkinson’s disease.
(1)
When an electrical impulse travels down the length of a neuron – from the
receiving dendrite, through the cell body, and down the transmitting axon – it
triggers the release of packets of neurotransmitters into the synaptic
gap. These transmitters hook onto receptors of the next neuron, triggering
an electrical impulse which then travels down that neuron, causing yet another
transmitter release. What Knoll and colleagues discovered through their highly
technical experiments is that DPR and PEA act to more efficiently couple the
release of neurotransmitters to the electrical impulse that triggers their
release. (2,16)
In other words, DPR (and PEA) cause a larger release of transmitters in
response to a given electrical impulse. It’s like “turning up the volume”
on CA nerve cell activity. And this may be clinically very useful in
various contexts – such as Parkinson’s disease and Alzheimer’s disease, where
the nigrostriatal tract (PD) and MLC circuits (AD) under-function (1,17), as
well as in depression, where they may be under-activity of both DA and NA
neurons. (18,19)
Knoll’s research also indicates that after sexual maturity the activity of
the CA nervous system gradually declines, and that the rate of decline
determines the rate at which a person or animal ages. (10,20) Knoll therefore
believes that DPR’s CAE effect explains its anti-aging benefit. (10,20)
Knoll also believes that DPR’s CAE activity is independent of its MAO-B
inhibition effect, because in rats he has shown CAE effect at doses considerably
lower than that needed to achieve MAO-B inhibition.
Knoll’s work indicates that PEA is also a CAE substance. (16) PEA is a
trace amine made in the brain that modulates (enhances) the activity of DA/NA
neurons. (16,21) Autopsy studies have shown that while DPR increases DA levels
in Parkinson patient brains by only 40-70%, DPR increases PEA levels 1300 –
3500%! (14,22) PEA is the preferred substrate for MAO-B, the MAO that DPR
inhibits. Paterson and colleagues have shown that PEA has an extremely
rapid turnover due to its rapid and continuous breakdown by MAO-B. (21)
Thus DPR’s CAE activity has a dual mode of action. At low, non-MAO-B
inhibiting doses, DPR has a direct CAE activity.
At higher, MAO-B inhibiting doses, DPR creates an additional CAE effect, due
to the huge increases in brain PEA levels that DPR causes, PEA also being a CAE
substance. Many authors have pointed out the probable DA neuron activity
enhancing effect of PEA in Parkinson patients taking DPR. (14, 15, 22)
Knoll’s discovery of PEA’s CAE effect now explains this PEA DA-enhancing
effect.
DEPRENYL: THE NEUROPROTECTOR
DPR has been shown to protect nerve cells from an ever-growing list of
neurotoxins. Some of these neurotoxins can actually be produced within the brain
under certain conditions, while others come from the environment or diet.
MPTP is a chemical first identified as a contaminant in synthetic
heroin. In the 1980s young men using synthetic heroin suddenly developed a
Parkinson-like disease. It was then discovered that the MPTP was taken up
by glial cells surrounding nigrostriatal neurons, where it was converted by
glial MAO-B enzymes into the real toxin, MPP . The nigral neurons then
absorbed MPP into their mitochondria, where MPP poisoned the mitochondria,
killing the DA-using neurons.(15) The MAO-B inhibiting dose of DPR (10 mg/day)
has been shown to prevent MPTP from being converted to the neurotoxin
MPP .(4) And as Lange and colleagues note, “Compounds with a chemical
structure similar to MPTP include both natural and synthetic products (e.g.
paraquat) that are used in agriculture!” (15)
6-hydroxydopamine (6-OHDA) is a potent neurotoxin that can spontaneously form
from DA in DA-using neurons. (11,13) 6-OHDA may then further auto-oxidize to
generate toxic superoxide and hydroxyl free radicals and hydrogen peroxide.
(11,13) Knoll’s research has shown that pre-treatment of striatal
DA-neurons with DPR can completely protect them from 6-OHDA toxicity. (4,11,13)
Even in those not suffering from Parkinson’s disease, the nigrostriatal neurons
are the fastest aging neuron population in the human brain – an average 13% loss
every decade from the 40s on. (1,13) Knoll and others believe that 6-OHDA
neurotoxicity is a key cause of this “normal” nigral death, and that DPR may be
“just what the doctor ordered” to retard this debilitating downhill neural
slide.
DSP-4 is a synthetic NA-nerve toxin. In rodents DPR has been shown to prevent
the depletion of NA in NA-using neurons and NA-nerve degeneration that DSP-4
causes. (4) AF64A is a cholinergic toxin – it damages brain cells that use
acetylcholine. DPR pre-treatment has been shown to protect cholinergic neurons
from AF64A toxicity. (4)
DPR has also protected human nerve cells from peroxynitrite and nitric oxide
toxicity. Peroxynitrite is formed naturally in the brain when nitric oxide
reacts with superoxide radical. Peroxynitrite causes “apoptosis”, a programmed
“suicide” cell death that can be triggered in neurons by various agents. DPR was
found to inhibit peroxynitrite-caused apoptosis, even after the DPR was washed
from DPR pre-treated cells. (3)
Methyl-salsolinol is another MAO-B produced endogenous neurotoxin. Salsolinol
is a tetra-hydroisoquinoline produced from the interaction of DA and
acetaldehyde, the first-stage breakdown product of alcohol.
Once formed, salsolinol can then be further modified by MAO-B to generate
methyl-salsolinol. DPR’s MAO-B inhibiting activity can prevent the DNA damage
caused by this toxin. (3,4)
By inhibiting MAO-B, DPR reduces the toxic load on the brain that is
routinely produced through the normal operation of MAO-B. MAO-B digests not just
DA and PEA, but also tryptamine, tyramine and various other secondary and
tertiary amines. (15)
As noted earlier, PEA is the substance MAO-B is most efficient at digesting,
so that the half-life of PEA is estimated at only 0.4 minutes. (21)
This continuous high level breakdown of PEA (and other amines) produces
aldehydes, hydrogen peroxide and ammonia as automatic MAO-B reaction products,
and they are all toxins. (4) Thus by reducing age-elevated MAO-B activity, DPR
reduces the toxin burden on DA/NA neurons (where PEA is primarily produced).
“…L-deprenyl provides neuroprotection against growth factor withdrawal in
PC12 cells, oxidative stress in mesencepahalic neurons, and the genotoxic
compound, Ara C, in cerebellar granule neurons, and against axotomy-induced
motoneuronal degeneration and delayed neuronal death in hippocampus after global
ischaemia.” (24) And these are just some of the many reports in the scientific
literature on DPR’s versatile neuroprotection.
DEPRENYL: PARKINSON’S DISEASE
Parkinson’s disease (PD) is one of the two major neurodegenerative diseases
of the modern world – Alzheimer’s disease is the other. PD affects up to 1% of
those over 70, a lesser percent of those 40-70, and rarely anyone below 40. (23)
PD is caused by a severe loss of DA-using nigrostriatal neurons, with symptoms
manifesting after 70% neuronal loss, and death usually ensuing after 90% loss.
(23)
The physiologic role of the nigral neurons is the continuous inhibition of
the firing rate of the cholinergic interneurons in the striatum. (13) When
the nigral neurons fail in this negative feedback control, voluntary movement
and motor control is “scrambled,” leading to the typical PD symptoms: shuffling
gait, stooped posture, difficulty initiating movement, freezing in mid-movement,
and the “shaking palsy.” By the late 1960’s the standard treatment for PD
was the amino-acid precursor of DA, L-dopa. The L-dopa increased the DA levels
in the few remaining nigrostriatal neurons in PD patients (80% of brain DA is
normally located in nigral neurons(11), thus at least partially restoring normal
movement and motor control.
However by 1980 A. Barbeau, after analyzing results of 1052 PD patients
treated over 12 years, wrote that “long-term side effects are numerous….
although we recognize that levodopa is still the best available therapy, we
prefer to delay its onset until absolutely necessary.” (1)
DPR became a standard therapy to treat PD by the late 1970’s. In 1985
Birkmayer, Knoll and colleagues published a paper summarizing the results of
long term (9 years) treatment with L-dopa alone or combined with DPR in PD. (25)
They found a typical 1 to 2 year life extension over the average 10 years from
L-dopa onset until death in the L-Dopa/DPR group. The 1996 DATATOP study found
that; “To the extent that it is desirable to delay levodopa therapy, deprenyl
remains a rational therapeutic option for patients with early PD.” (26) In
a 1992 paper Lieberman cited 17 studies supporting the claim that “… with
levodopa-treated patients with moderate or advanced PD… the addition of
selegiline [DPR] is beneficial.” (6) Thus by the 1980s-1990s DPR had become a
standard PD therapy, used either to delay L-dopa use, or in combination with
L-dopa. Yet in 1995 a report published in the British Medical Journal seriously
questioned the use of DPR in combination with L-dopa to treat PD. (27)
The UK-PD Research Group study followed 520 PD patients for 5-6 years.
Several hundred patients initially received 375 mg L-dopa, while several hundred
others received 375 mg L-dopa plus 10 mg DPR daily. After 5-6 years, the
mortality rate in the L-Dopa/DPR group was almost 60% higher than in the L-dopa
only group. The study authors therefore recommended DPR not be used in PD
treatment. Yet the UK-PD study is the only one ever to find increased mortality
with DPR use in PD, and the study has been severely criticized on multiple
grounds by various PD experts. In response to the study, the BMJ published 8
letters in 1996 criticizing the study on various methodological and statistical
grounds. (28) And a 1996 Annals of Neurology article by 4 PD experts provided an
exhaustive analysis of the BMJ study, raising many questions and criticisms.
(29) One key criticism is that the UK-PD study was open label and patients could
be reassigned to treatment groups during the study. 52% of the L-dopa group and
45% of the L-Dopa/DPR group changed treatment groups, yet the allocation of end
points (deaths) was based on patients’ original drug assignment, regardless of
which drugs the patient was actually taking at time of death! When the death
rate was compared only between those remaining on their original drug
assignment, there was no statistically significant difference in mortality
between the L-dopa and DPR/L-Dopa groups.
Another criticism levelled against the UK study is based on the dosage of
L-dopa. It is generally accepted that DPR reduces L-dopa need by about 40%.
(14) Thus, to achieve bio-equivalent L-dopa doses, the DPR/L-Dopa group
should have only received 225 mg L-dopa, compared to 375 mg in the L-dopa only
group. As evidence that the initial L-dopa dose was too high in the DPR/L-Dopa
group, after 4-5 years the median L-dopa dose remained at 375 mg in the DPR
group, while it had increased to 625 mg in the L-dopa only group. And a growing
body of evidence has shown L-dopa to be neurotoxic in PD patients. In a 1996
review paper, S. Fahn briefly reviews 20 in vitro and 17 in vivo studies showing
L-dopa to be toxic, especially in neurologically compromised, oxidant-stressed
individuals, such as PD patients. (30) Thus if there were any real
increased mortality in the DPR/L-Dopa group in the UK study, it is more likely
due to L-dopa toxicity than DPR. This is further borne out by a 1991 study by
Rinne and colleagues, who studied 25 autopsied PD brains. (31) When they
compared the substantia nigra of 10 patients who had received L-dopa plus DPR
with 15 patients who had received L-dopa only, they discovered that there were
significantly more nigral neurons remaining in the DPR/L-Dopa brains, i.e. the
DPR had actually acted to preserve nigral neurons from L-dopa toxicity. Olanow
and co-authors conclude their paper reviewing the UK study: “It is our opinion
that the evidence in support of discontinuing selegiline [DPR] in
levodopa-treated patients, because of fears of early mortality, is not
persuasive. Accordingly, we do not recommend that selegiline be withheld in PD
patients based solely on the results of the UK study.” (29)
DEPRENYL: ALZHEIMERS DISEASE
Alzheimer’s disease (AD) is the most widespread neurodenerative disease of
modern times, affecting several million people in the U.S. alone. AD is
characterized not only by severe memory loss, but by verbal dysfunction,
learning disability and behavioral difficulties – even hallucinations. AD is
known to involve damage to the cholinergic neurons of the hippocampus, but “In
[AD], in addition to the reduction of acetylcholine, alterations have been
observed in the activities of other neurotransmitters. More specifically, the
deterioration of the dopaminergic [DA] and noradrenergic [NA] systems… seems
particularly relevant to the cognitive manifestations…. cerebral depletion of
dopamine (DA) can easily lead to memory and attention deficits. In [AD] there is
significant increase in type-B cerebral and platelet monoamine oxidases
(MAO-Bs)…. [Therefore] pharmacological inhibition of MAO-B could result in an
improvement in the cognitive functions normally mediated by the
catecholaminergic systems.” (17)
Thus, with its combined MAO-B inhibition effects and catecholamine activity
enhancing effects, DPR would seem “tailor-made” to treat AD. And indeed that is
the conclusion of a 1996 review paper on AD and DPR.
Tolbert and Fuller reviewed 4 single-blind and 2 open label DPR trials in AD,
as well as 11 double-blind DPR/AD studies. (7) They noted that all 6
single-blind/open label studies reported positive results, while 8 of the 11
double-blind studies reported favorable results, typically with a 10 mg DPR/day
dosage. In 3 of the single-blind studies DPR was compared to 3 “nootropics” –
oxiracetam, phosphatidylserine and acetyl-L-carnitine – and was superior to all
3. Tolbert and Fuller were so impressed with DPR that they concluded “…in our
opinion, selegiline is useful as initial therapy in patients with
mild-to-moderate Alzheimer disease to manage cognitive behavioral symptoms. In
patients with moderate-to-severe Alzheimer disease, selegiline’s efficacy has
not been adequately assessed; however, given the lack of standard treatment,
selegiline should be considered among the various treatment options.” (7)
DEPRENYL: DEPRESSION
DPR has been used experimentally as a treatment for depression since the late
1970s. While the causes of depression are diverse and still under investigation,
it is by now accepted that dysfunction of DA and NA neural systems is a frequent
biochemical cause of depression. (18,19)
In addition the research of A. Sabelli and colleagues has established that a
brain PEA deficiency also seems to be strongly implicated in many cases of
depression. (32) Given that DPR is a catecholamine (DA and NA) activity
enhancer, and that DPR strongly increases brain PEA through MAO-B inhibition,
DPR would seem a rational treatment for depression.
Studies with atypical depressives (33), treatment-resistant depressives (34),
and major depressives (35) have shown DPR to be an effective, low side-effect
depression treatment. However, such studies have often required DPR dosages in
the 20-30, even 60 mg range. While these dosages caused little problem in
short-term studies, it is dubious to consider using such high, non-selective
MAO-B inhibition doses for long term (months – years) treatment. Three studies
have shown antidepressant promise at selective, MAO-B inhibiting doses.
In 1978 Mendelwicz and Youdim treated 14 depressed patients with 5 mg DPR
plus 300 mg 5-HTP 3 times daily for 32 days. (1) DPR potentiated the
antidepressant effect of 5-HTP in 10/14 patients. 5-HTP enhances brain serotonin
metabolism, which is frequently a problem in depression (37), while DPR enhances
DA/NA activity. Under-activity of brain DA, NA and serotonin neural systems are
the most frequently cited biochemical causes of depression (18,19,37), so DPR
plus 5-HTP would seem a natural antidepressant combination.
In 1984 Birkmayer, Knoll and colleagues published their successful results in
155 unipolar depressed patients who were extremely treatment-resistant.
(8) Patients were given 5-10 mg DPR plus 250 mg phenylalanine daily.
Approximately 70% of their patients achieved full remission, typically within
1-3 weeks. Some patients were continued up to 2 years on treatment without loss
of antidepressant action. The combination of DPR plus phenylalanine enhances
brain PEA activity, while both DPR and PEA enhance brain catecholamine activity.
Thus DPR plus phenylalanine is also a natural antidepressant combination.
In 1991 H. Sabelli reported successful results treating 6 of 10
drug-resistant major depressive disorder patients. (9) Sabelli used 5 mg DPR
daily, 100 mg vitamin B6 daily, and 1-3 grams phenylalanine twice daily as
treatment. 6 of 10 patients viewed their depressive episodes terminated within
2-3 days! Global Assessment Scale scores confirmed the patients’ subjective
experiences. Vitamin B6 activates the enzyme that converts phenylalanine to PEA,
so the combination of low-dose DPR, B6, and phenylalanine is a bio-logical way
to enhance both PEA and catecholamine brain function, and thus to diminish
depression.
DEPRENYL: THE ANTI-AGING DRUG
4 series of rat experiments, as well as an experiment with beagle dogs, have
shown that DPR can extend lifespan significantly, even beyond the “technical
lifespan” of a species. Knoll reported that 132 Wistar-Logan rats were treated
from the end of their second year of life with either saline injections or 0.25
mg/kg DPR injection 3 times weekly until death. (11)
In the saline-treated group the oldest rat reached 164 weeks of age, and the
average lifespan of the group was 147 weeks. In the DPR group, the average
lifespan was 192 weeks, with the shortest-living rat dying at 171 weeks, and the
longest-lived rat reaching 226 weeks.
In a second series of experiments Knoll treated a group of 94
“low-performing” (LP) sexually inactive male rats with either saline or DPR
injections (0.25 mg/kg) from their eighth month of life until death. (11) Knoll
had already established a general correlation between sexual activity status and
longevity in the rats. The saline-treated LP rats lived an average 135 weeks,
while the DPR-treated LP rats averaged 153 weeks of life. The saline treated HP
rats lived an average 151 weeks of life, while the DPR -treated HP rats averaged
185 weeks of life, with 17/50 HP-DPR rats exceeding their estimated technical
lifespan of 182 weeks. (20)
Knoll’s experiments were partially replicated by Milgram and co-workers and
Kitani and colleagues. (11) Milgram’s group used shorter-living Fischer
344 rats, while still starting DPR treatment at 2 years of age – in effect later
in their lives – and found a marginally significant 16% lifespan extension. The
Kitani group, also using the shorter-lived Fischer rats, started their DPR
treatment at 1.5 years of age, and found a 34% life increase.(11)
Ruehl and colleagues performed an experiment with beagle dogs and DPR,
administered at 1 mg/kg orally per day, for up to 2 years 10 weeks. In a subset
of the oldest dogs tested (10-15 years of age), 12 of 15 DPR-treated dogs
survived to the conclusion of the study, while only 7 of 18 placebo-treated dogs
survived. By the time the first DPR-treated dog died on day 427 of the study, 5
placebo-treated dogs had already died, the first at day 295. (12) Ruehl et
al note that “dogs provide an excellent model of human aging,” so their study
takes on added significance.
Knoll has repeatedly emphasized that the nigrostriatal tract, the tiny
DA-using nerve cluster in the basal ganglia (“old brain”), typically dies off at
an average rate of 13% per decade starting around age 45 in humans.
This fact literally sets the human technical lifespan (maximum obtainable by
a member of a species) at about 115 years, since by that age the nigral neuron
population would have dropped below 10% of its original number, at which time
death ensues even if in all other respects the organism were healthy. (23) Based
on the sum total of the animal DPR literature, as well as the 1985 study showing
life-extension in DPR-treated PD patients (25) Knoll has suggested that if DPR
were used from the 40s on, and only modestly lowered the nigrostriatal neuron
death rate – i.e. from 13% to 10% per decade – then the average human lifespan
might increase 15 years, and the human technical lifespan would increase to
roughly 145 years. (23)
After 45 years of research, Knoll has concluded that “…the regulation of
lifespan must be located in the brain,” (20) His research has further convinced
him that “… it is the role of the catecholaminergic neurones to keep the
higher brain centres in a continually active state, the intensity of which is
dynamically changed within broad limits according to need.” (20) Knoll’s
research has shown that catecholaminergic nerve activity reaches a maximum at
sexual maturity, and then begins a long, gradual downhill slide thereafter.
Knoll’s animal research has shown catecholaminergic activity, learning ability,
sexual activity and longevity to be inextricably interlinked. (11,20)
Knoll argues that the quality and duration of life is a function of the
inborn efficiency of the catecholaminergic brain machinery, “i.e. a high
performing longer living individual has a more active, more slowly deteriorating
catecholaminergic system than [his/her] low performing, shorter living
peer.”(20) And his key conclusion is that “… as the activity of the
catecholaminergic system can be improved at any time during life, it must be
essentially feasible to … [transform] a lower performing, shorter living
individual to a better performing, longer living one.” (20)
It is on this basis that Knoll consistently, throughout his DPR papers
(11,20,23), recommends the use of 10 – 15 mg oral DPR/week, starting in the 40s,
to help achieve this goal in humans. Knoll’s research clearly convinces him that
DPR is both a safe and effective preserver of the nigrostriatal tract, as well
as a catecholamine activity enhancer. DPR may not be the ultimate anti-aging
drug, but it is one that is safe and effective, well validated theoretically and
experimentally, and it’s available now.
DEPRENYL: DOSAGE & SIDE-EFFECTS
Both Dr. Joseph Knoll and the Life Extension Foundation (37) recommend a
10-15 mg weekly (i.e. 1.5 – 2 mg/day) oral DPR dosage for humans, starting
around age 40, possibly even in the 30s. 10 mg/day is a relatively standard DPR
dose for treatment of PD and AD, but this higher dose should only be used with
medical supervision. Some DPR experts believe this dosage is excessive, and that
with long term DPR use lower doses may still be effective and safer. (22)
Knoll has noted that the human MAO-B inhibiting DPR dose ranges from 0.05 to
0.20 mg/kg of bodyweight. (1) Thus, even in those wishing to use DPR at an
effective MAO-B inhibiting dose, it should not be necessary to use more than 3-5
mg/day. Because DPR is a potent and irreversible MAO-B inhibitor, it may even
turn out in many individuals that the suggested 1.5-2 mg/day “life extension”
DPR dose may achieve MAO-B inhibition with long term use.
DPR is reported in most human studies to be well tolerated. (7) Typically, no
abnormalities are noted in blood pressure, laboratory valves, ECG or EEG.
(7)
The most common side effects reported for DPR are gastrointestinal symptoms,
such as nausea, heartburn, upset stomach, etc. (7) Some studies have found side
effects such as irritability, hyper-excitability, psychomotor agitation, and
insomnia, (7,8) These effects are probably due to DPR’s
catecholamine-enhancing effect, over-activating DA/NA neural systems at the
expense of calming/sleep-inducing serotonergic systems, so taking magnesium and
tryptophan or 5-HTP may suffice to counter these “psychic” effects.
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