Wednesday, June 23, 2010

Selegiline and Lifespan Extension

Deprenyl increases the lifespan of female hamsters.
Deprenyl increases the lifespan of female hamsters. (Photo by MarinaAvila)

Selegiline, also known as deprenyl, is an old life extension drug. It's been around since the 80's, but after some conflicting data from Parkinson's Disease studies, interest in selegiline for life extension purposes has been negligible.

These days, deprenyl is mostly used to treat Parkinson's Disease, depression and dementia. Still, the early studies showed such promising results that a review of the studies on deprenyl and longevity is in order.

Deprenyl extends maximum lifespan in male rats

In the first study on selegiline and lifespan, 24-month old male Wistar-Logan rats were treated subcutaneously with selegiline (0.25 mg/kg) or saline solution three times a week (link). The control group receiving only saline had an average lifespan of 147 weeks, about 34 months. The longest living rat in this group was 164 weeks (~37 months) old.

The deprenyl group did significantly better. In fact, even the shortest living rat receiving selegiline managed to outlive the longest living in the control group, making it to 171 weeks (~39 months). The longest living rat survived for a whopping 226 weeks (~52 months). That's a maximum lifespan increase of 38%. The average lifespan in the deprenyl group was 198 weeks (~46 months). The author, Dr. Joseph Knoll, states:

The average lifespan was higher than the estimated maximum age of death in the rat (182 weeks). This is the first instance that by the aid of a well-aimed medication members of a species lived beyond the known lifespan maximum.

In 1994, Dr. Knoll continued his experiments, again using the same dosing but this time on younger Wistar-Logan rats (28 weeks, or ~6 months old), some of which were sexually inactive and some of which were sexually highly active (link).

The sexually inactive control rats remained inactive throughout their life and lived 135 weeks (~31 months), whereas their deprenyl-treated peers suddenly developed a hunger for sex and lived 152 weeks (~35 months), the same as the sexually active control group. The highly active rats given deprenyl became even more sexually active than their saline-treated control group, and lived for 185 weeks (~43 months).

Only mean lifespan increases in another strain of rats

Between Knoll's experiments on male Wistar-Logan rats, another lifespan experiment on selegiline was done. This time, male Fischer rats were given deprenyl (0.25 mg/kg) or saline subcutaneously every other day, starting at 23 to 25 months of age (link).

Again, the deprenyl group lived longer, but this time the effect was not as dramatic as in the previous study. The remaining life expectancy of rats given selegiline was increased by only 16%. Then again, as Ben Best points out in his good summary of deprenyl, Fischer rats live only 28 months, much shorter than Wistar-Logan rats.

In 1993, Japanese scientists doubled the standard dose of deprenyl and injected male Fischer rats with 0.5 mg/kg, starting from the age of 18 months (link). The abstract states:

The increases in average life expectancies caused by deprenyl treatment (15% from 18 months and 34% from 24 months) were both statistically significant.

I don't have access to the full paper, so I'm not sure what exactly they mean by this. Were there actually two treated groups, with one given deprenyl since 18 months and the other since 24 months of age, or did the control group start dropping dead faster after 24 months?

In any case, maximum lifespan was apparently not increased, unlike in the previous studies. A possible explanation is the shorter lifespan of Fischer rats and the higher dose used. On the other hand, Ben Best says on his website:

At the 2004 American Aging Association Conference Kitani (one of the authors of the Fischer study) reported that he had halved the dose to the standard 0.25mg/kg (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.

If the above is correct, then the higher dose is probably not the culprit. Perhaps treatment has to be begun earlier, or perhaps deprenyl doesn't work in all rat strains.

Different doses and forms of deprenyl

In 1992, two more studies appeared in a Hungarian journal, with Dr. Knoll as the coauthor in both of them. The first one fed male mice either deprenyl, Dinh lang root extract or a combination of the two three times a week, starting at 12 months of age (link). The abstract states only that the combination was the most potent treatment, increasing both memory function and survival time.

The second study used the same dosage of deprenyl as before, but this time 6-month old male Wistar rats and a different form of deprenyl known as (-)p-fluoro-deprenyl were used (link). The study lasted for 25 months. Three of the 20 control rats (15%) and 15 of the 40 deprenyl-treated rats (37.5%) survived until the end. Three of the rats receiving selegiline were still sexually active at 31 months, even though normal male Wistar rats lose their ability to ejaculate by the time they're 2 years old.

The authors also experimented with a much smaller dose of selegiline, giving 13-month old non-copulator rats only 0.01 mg/kg instead of the usual 0.25 mg/kg. The lifespan of these rats was short, with the control group living only 102 weeks (~23 months) and the (-)p-fluoro-deprenyl group living 106 weeks (~24 months). Rats given the standard deprenyl lived for 104 weeks. Sexual performance was improved in both deprenyl groups, however.

Deprenyl in females, mice, and dogs

The first study on selegeline and life extension on female rats came a few years later. Once again, the dosing was 0.25 mg/kg injected three times a week (link). The rats were 6 months old and had their ovaries removed. All the control females were dead before hitting 15 months of age, while all of the deprenyl-treated rats were still alive. Three of them even reached 36 months of age. Unlike in the case of males, however, neither group showed much sexual activity.

In Syrian hamsters, a low dose of selegiline increased the lifespan of females but not males, even though MAO-B was inhibited in both groups by the same amount (link). Female controls died younger than male controls, but in the deprenyl group this difference disappeared.

Deprenyl seems to increase lifespan also in immunosuppressed mice. When 4 mg of selegiline was mixed in 10 kg of feed, survival improved dramatically (link). The last mouse in the control group died 2.5 months after the study was started, at the age of 5 months, whereas the last mouse in the selegiline group made it to 14.5 months.

Deprenyl and dogs

Rodents are not the only animals that seem to gain extra years from selegiline. A study on beagle dogs, ranging in age from 2.8 to 16.4 years, studied the effects of orally administered deprenyl on lifespan (link). The dose was 1 mg/kg, four times as high as the one originally used by Dr. Knoll on rats.

The study lasted for 2 years and 10 weeks. Almost all of the young dogs survived until the end of the study, but older dogs given deprenyl survived longer than those that were given placebo. 80% of dogs in the deprenyl group survived until the end of the study, compared to only 39% in the placebo group. The first deprenyl-treated dog died on day 247, whereas the first untreated dog died on day 295.


In the experiments of Dr. Knoll, who first discovered its life-extending properties, selegiline consistently increased the mean and maximum lifespan of male Wistar-Logan rats. The rats given deprenyl had a maximum lifespan that was up to 38% greater than that of the control rats. The longest living rat in these studies was 52 months old. Only one study looked at female rats and life extension, but it too showed an increased lifespan from deprenyl.

Extrapolating directly from rats, the 0.25 mg/kg dose used in the experiments would correspond to 20 mg of selegiline every other day, or 10 mg daily, for a man weighing 80 kg (~176 pounds). For a female weighing 60 kg (~132 pounds), the equivalent would be 7.5 mg daily.

Not all of the results have been so uniformly positive, however. While mean lifespan was increased in male Fischer rats, maximum lifespan was not. One possible reason is the shorter average lifespan of Fischer rats, but other explanations cannot be ruled out. Also, male Syrian hamsters given deprenyl did not live longer, although females did.

For more information on life extension, see these posts:

Does Intermittent Fasting Increase Lifespan?
How Do People Feel about Life Extension?
Dietary Supplement Increases Lifespan by 11% in Healthy Mice
Slowing Down Aging with Intermittent Protein Restriction

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3 kommenttia:

Med Dog July 26, 2010 at 3:36 AM  

"Beneficial effects of natural antioxidants EGCG and alpha-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditis elegans."

"Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span."

"Dietary supplementation with (R)-αα-lipoic acid reverses the
age-related accumulation of iron and depletion of
antioxidants in the rat cerebral cortex"

You MUST address alpha-Lipoic Acid! THIS STUFF IS CRAZY!! GSH levels upped everywhere!

JLL July 27, 2010 at 1:37 PM  

@Med Dog,

I've only skimmed through the studies on ALA, but it does look interesting. I know people took ALCAR + ALA for quite a while, but the second study you posted scared most of them off ALA:

"When animals are switched from DR feeding to ad libitum feeding with a diet supplemented with alpha-lipoic acid, the extended survival characteristic of DR feeding is maintained, even though the animals show accelerated growth. Conversely, switching from ad libitum feeding a diet supplemented with alpha-lipoic acid to DR feeding of the non-supplemented diet, blocks the normal effect of DR to extend survival, even after cessation of lipoic acid supplementation."

The idea that you could go on CR for a while, take ALA, and then go back to eating all you want while retaining all the benefits of CR sounds great, but what if something goes wrong? The above is so strange that I would hesitate to take large doses of ALA until we know more.


Anonymous August 18, 2010 at 5:57 AM  

Hi, you can´t extrapolate using weight only due to rats have a higher metabolism, so the dose is lower for humans.

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