By Benjamin V. Treadwell, Ph.D.

Our children and grandchildren continually remind us of our younger days, when we could perform physical and mental feats with seemingly no effort or fatigue. So, why the age-related loss of energy? And can we do anything to stop or attenuate its progression? Recent research suggests the answer to the second question is “yes.” But first questions first.

More Age, Less Energy
Those grandchildren are quick, physically and mentally, due to their cells’ superb efficiency at converting food to energy and maintaining ample energy reserves. But, as part of the aging process, the health of important cellular constituents deteriorates. As a consequence, so does our cells’ capacity to produce energy.

Perhaps the most important biochemical pathways to be affected by aging are those associated with the cellular structures, the mitochondria. The mitochondria provide virtually all the energy the cells of our body need to stay healthy and active. And having enough energy stored in the cell is like having enough fuel to heat your home during those bitter-cold winter days…you can’t survive without it!

There are some steps we slower, older folks can take to support energy production by our mitochondria. (See Juvenon Health Journals Mitochondria: Regulators of Cell Death and Longevity; Alpha Lipoic Acid: Less Cellular Stress, More Energy; The Carnitine Cousins.) This month’s Journal presents information that suggests there are also things we can do to help redirect limited cellular energy stores in aged tissues, making them available to more vital cellular processes.

Highest Energy Consumer
The cells most affected by the age-related decline in energy production are, naturally, those with the highest energy requirements. The brain needs to produce more energy than any organ in the body, even during sleep. The nervous system requires the bulk of this energy to synthesize signaling molecules (neurotransmitters) and cellular pumps to facilitate the transport of ions (salts) into and out of the cell (neuron) for the maintenance of electrical charge.

Because of this high energy demand, the central nervous system must have a consistent, as well as sufficient, supply of energy to maintain optimum health. An energy deficit can result in the death of neurons, culminating in a dysfunctional nervous system.

Deficit Defense
But what can we do, especially as we age, to support the nervous system’s energy needs? Studies seem to indicate a form of vitamin B3, nicotinamide, could help.

Nicotinamide is required for the synthesis of a molecule, nicotinamide adenine dinucleotide (NAD), which is essential for the production of energy in the mitochondria. NAD is not only important for energy production, but is also necessary for the synthesis of the building blocks of our genetic code, as well as the repair of damage done to the DNA comprising the code.

NAD-intensive Stress
What causes this DNA damage?

Previous and recent work has shown what happens during cerebral ischemic events (strokes). At the biochemical level, an increase in the production of oxidants leads to damage to cellular structures, much of it to the genetic material. The DNA damage causes activation of specific enzymes, PARP (polyA ribose polymerase) and SIRT1. These cellular “machines” utilize large amounts of the high-energy-containing NAD molecule to repair and protect the DNA.

Other stress-producing events occur to the nervous system with increased frequency as we age. They are associated with elevated levels of toxic substances, such as free radicals and other reactive oxygen species, in the cell. These substances have been shown to super-excite neurons by acting to cause the release of the neurotransmitter, glutamate, in excess amounts.

Although glutamate is important for the transmission of nerve impulses, when produced in excess, it can lead to an electrically over-excited neuron (commonly referred to as glutamate excitotoxicity). This over-excited state results in the neuron’s uptake of charged substances, ions such as calcium and sodium, in an attempt to restore normal ionic balance. Unfortunately for the neuron, the process takes enormous energy and, if the energy store is compromised – for example, by the low levels of NAD common in the elderly – the cell dies.

Saving the Neurons
Vitamin B3 to the rescue? A series of articles has reported on the effects of administering nicotinamide to animals, or cells in culture, that were under the type of NAD-depleting stress as described above.

Most recently, a mouse model for cerebral stroke demonstrated a decrease in NAD, coinciding with an increase in damage to brain tissue. The damage was significantly less in those animals receiving vitamin B3. The vitamin, a precursor for NAD, was shown to stimulate synthesis of this high-energy molecule, as well as inhibit the activation of the SIRT1 enzyme that consumes NAD. The net effect? An increase in the energy molecule and the restoration of energy balance in those neurons affected by the stroke. (See this month’s “Research Update.”)

Additional research has shown the potential benefits of administering nicotinamide to animals engineered to develop symptoms of Alzheimer’s disease. Those fed this form of vitamin B3 had significantly fewer symptoms of the neurodegenerative disease than those receiving a placebo. The mechanism, although not yet completely understood, appears to affect either the PARP enzyme, the SIRT1 enzyme, or both.

Another interesting hypothesis proposes that over-excited neurons may cause specific types of migraine headache. There is some evidence, although not yet compelling, that nicotinamide may be of help with this central nervous system-related condition.

Potential Health Benefits
The work described above is encouraging. Further results, from these and future studies, may provide information to help reduce age-associated susceptibility to cerebral stroke. It may even be the key to preventing conditions that affect the nervous system, like Alzheimer and Parkinson’s diseases.

In the meantime, nicotinamide is a relatively safe compound when taken in low doses (less than 500 mg per day), but can cause liver damage when taken in high doses by susceptible individuals. Consulting with your health professional is recommended.

A recently published paper, “Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons,” sheds new light on the association of cellular energy and disease. Investigators at the National Institute on Aging, Laboratory of Neuroscience, in Baltimore, MD, detail their work related to neurons and the vitamin B3-containing molecule, NAD.

Previous experiments had implicated a lack of sufficient energy supplies in neurons as a causative factor for the development of many of the common age-associated conditions of the nervous system, including Alzheimer’s, Parkinson’s and stroke. The new research has identified NAD as a key energy molecule within the neurons, required for numerous biochemical pathways, critical as a cofactor in mitochondrial energy production and to maintaining cellular health and life.

With a mouse model of cerebral stroke, the investigators demonstrated that, when the cells of the brain were confronted with stress, they responded by becoming overly active, or excitotoxic, in an attempt to correct the damage. Further, the cells of the damaged area of the brain were depleted of the energy molecule, NAD.

Speculating that this could be the consequence of the activation of either PARP (polyADP ribose polymerase) or SIRT1 (silent information regulator of transcription), the investigators examined the role of these two cellular repair enzymes. They hypothesized that PARP and/or SIRT1 were consuming the NAD and, consequently, causing cells to die.

The researchers experimented with administering nicotinamide (vitamin B3), believed to have the capacity to stimulate the synthesis of NAD, as well as inhibit the activity of the NAD-consuming enzymes. In addition to an increase in levels of NAD, the animals receiving the vitamin B3 showed a significant attenuation of neuronal cell damage and cell death.

This study supports reducing the activities of certain energy-demanding enzymes to help prevent life-threatening energy deficits. It might also be interpreted as an “energy-triage” approach, where energy is directed to those processes more vital to the cell until the supply can be replenished.

Read article abstract here.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

question: I’d like to know if the combination of alpha lipoic acid and acetyl-L-carnitine helps promote weight loss? Secondly, I’ve read that acetyl-L-carnitine increases testosterone levels. Is this true? Thanks. – J

answer: We have not yet examined the effects of Juvenon on weight gain/loss in a controlled clinical study. However, some people, who take Juvenon, have reported an effect on reducing weight to some extent. I think this effect probably varies with different people, depending on gene profile and metabolism. Regarding your second question, I’m not aware of any published data that shows acetyl-L-carnitine increases testosterone levels in humans. 

Send your questions to AskBen@juvenon.com.
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Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon’s Scientific Advisory Board.