Deprenyl and Longevity Deprenyl, or l-selegiline, is a drug that was originally developed as an antidepressant. It blocks or inhibits the action of monoamine oxidase B (MAO), an enzyme that breaks down neurotransmitters like dopamine and norepinephrine. Preventing the breakdown of dopamine by MAO raises synaptic levels of dopamine, and this action is useful in the treatment of disorders like Parkinson's disease wherein dopamine neurons become malfunctional. But in contrast to other drugs with similar structure, deprenyl has a multitude of unique properties that have led some doctors to label it as an "anti-aging" drug. And while it's not a fountain of youth, claims that it has anti-aging properties are very much grounded.

Multiple animal studies have implicated deprenyl as increasing longevity. For more than a decade Dr. J. Knoll, of the Semmelweis University of Medicine in Budapest, has done numerous studies in which he increased the average and maximum life spans of deprenyl-treated rats vs. controls. (1997: ~20% average lifespan increase (ALI), 1989: ~30% ALI, 1988: ~35% ALI). In another small study with elderly dogs, 1 mg per kg of deprenyl administered orally significantly increased survival rate after six months. 12 of 15 dogs in the deprenyl group were alive and 8 of 18 of the control group were alive at the end of the study. At the Veteran Affairs Medical Center in Denver, deprenyl adminstered to rats via their drinking water significantly increased function lifespan with respect to cognitive preformance. At the Central Institute for Mental Health in Germany, deprenyl increased longevity and improved long term memory in aged hamsters. Deprenyl increased average lifespan by ~35% vs. controls in rats at the Tokyo Metropolitan Institute of Gerontology. Thus, there is a great deal of evidence that deprenyl has the potential to increase lifespan.

Due to the fact that caloric restriction has been receiving much attention as a means to increase longevity, it has been suggested that deprenyl treatments might increase longevity by reducing the dietary intake of nutrients. However, comparison of bodyweight between experimental and control groups in the deprenyl studies negates this idea.

If deprenyl does increase longevity, by what mechanism does it accomplish this? Some studies have pointed to deprenyl's ability to activate the superoxide dismutase (SOD) and catalase antioxidant systems. Knoll found in 1989 that deprenyl increased rat SOD activity in the striatum. In vitro rat brain studies at the Neurodegenerative Diseases Research Centre in London found a significant increase in SOD mRNA with deprenyl administration. A Japanese study last year found that antioxidant enzyme activity was enhanced not only in brain tissues but also in the heart, kidneys, adrenal glands and the spleen. Upregulation of these endogenous antioxidant systems can theoretically increase one's average life expectancy, depending on the role of free radicals in the aging process.

Studying the role of MAO-B in normal brain metabolism, I, and others unknown to me, thought that deprenyl's ability to inactivate MAO-B in itself could influence longevity. MAO-B is responsible for breaking down dopamine, and in this breakdown process hydrogen peroxide is generated as a byproduct. Hydrogen peroxide has much oxidative capacity, and during normal brain metabolism the hydrogen peroxide generated might cause significant damage over the course of one's life. Theoretically, damage resulting from the generation of hydrogen peroxide could contribute to the aging process. Deprenyl's ability to inactivate MAO-B could reduce free radical damage and play a role in the longevity-increasing results obtained from experiments with deprenyl.

Recently it has been found that deprenyl intereferes with apoptosis signalling pathways, and the idea that deprenyl increases longevity through MAO-B inhibition has been subsequently downplayed. Deprenyl binds to an enzyme called GAPDH, and this leads to decreased synthesis of pro-apoptotic proteins (eg. BAX, c-JUN) and increased synthesis in anti-apoptotic proteins (eg. BCL-2, SOD, heat shock protein 70). This explains the pathway by which SOD is upregulated, and might alone explain deprenyl's propensity to increase longevity. Other drugs in the same class as deprenyl, propargylamines, have also been found to have this activity and ones that don't inhibit MAO-B will be tested soon. This will illuminate whether MAO-B inhibition is related to the increases in longevity seen with deprenyl.

Deprenyl is currently used clinically to treat Parkinson's disease. It possesses the property of "catecholamine activity enhancement," implying that it intensifies the response of dopamine neurons. A hallmark of Parkinson's is the failing ability of the brain to produce dopamine, and this intensification of dopamine neuron response slows the effects of the disease. In addition to Parkinson's, deprenyl might have efficacy in the treatment of Alzheimer's disease. There are numerous reports of its neuroprotectivity (eg. 1, 2).

More experimentation is necessary to ascertain deprenyl's ability to increase life span. Whether the animal data will correlate to humans is unknown. It will be difficult to figure out whether or not deprenyl would increase life span in healthy humans because it is primarily being used only on patients with dementia, and these patients already have a below-average life expectancy compared to other non-afflicted people of the same age. Despite the still-enigmatic sides of deprenyl's character and biochemical function, the animal studies are very promising. If the biochemistry behind deprenyl's ability to increase longevity in animals is made more clear, it could open up many doors for future anti-aging treatments.