By Benjamin V. Treadwell, Ph.D.

As we get older, our skin wrinkles and our energy level declines, along with our memory and cognitive ability. Many of us begin to develop age-associated diseases like Alzheimer’s, Parkinson’s and diabetes. Why is it happening?

Current studies continue to look for clues at the cellular level. How do the components and function of youthful and older cells differ and what causes these differences? Today’s investigators are discovering some interesting answers, guided largely by observations of the early pioneers in aging research.

Caloric Restriction in the 30s
One such observation, first reported over 70 years ago, described the health benefits of restricting the caloric intake of animals. By simply feeding them a little less per day, the animals’ life spans were increased by a whopping 40%.

This basic experiment in caloric restriction (CR) not only benefited the animals, but it was also instrumental in promoting the field of aging research. It demonstrated, for the first time, how a simple manipulation could affect longevity.

Free Radicals in the 50s
Twenty years later, another observation essential to aging research was made. Denham Harman postulated that cellular damage could be produced by free radicals, both from the environment in the form of radiation and toxic chemicals, and within the cell itself during the process of converting food to energy. The intracellular conversion process takes place in the tiny structures (organelles) known as the mitochondria.

Recognizing the relationship between free radicals, cellular damage and the mitochondria led to the formulation of the popular “Mitochondrial Theory of Aging.” Based on the premise that, as we age, the free-radical-induced cellular damage accumulates, the theory proposed that the accumulation, and associated mitochondrial damage, is responsible for the wrinkled skin, loss of mental function and physical energy, and other age-associated issues mentioned earlier. 

Fewer Calories, Less Damage
So what’s the connection between the hungry rat who lives longer (CR) and free-radical-induced mitochondrial damage? Cells isolated from a calorie restricted rat contained a higher percentage of healthy mitochondria, as well as a greater number per cell of these energy dynamos, than cells from the normally fed rat.

In other words, caloric restriction seems to be keeping the animal young by maintaining more youthful-like, energy producing cellular organelles, the mitochondria. However, the question still remains as to the mechanism(s) involved in producing this effect.

Fewer Calories, More Stimulation
There is significant scientific evidence to suggest that caloric restriction increases the number of mitochondria by activating genes involved in the synthesis of mitochondrial structural and functional components. According to a very recent report, one of the CR-activated enzymes has yet another function. SIRT1 stimulates genes responsible for producing the machinery necessary to remove cellular debris, including damaged mitochondria. (See this month’s “Research Update.”) 

After all, wouldn’t it be counter-productive to produce new energy machines without first making space for them? To put it another way, removing damaged, useless mitochondria is analogous to getting the old, broken refrigerator out of the house before having the new one delivered.

Cellular Housecleaning
Taking out the cellular “garbage” involves activating a process referred to as autophagy (self digestion). The cell’s disposal machinery partitions off the damaged mitochondria with a membrane, its “garbage bag.”

After a series of steps, the content of the garbage bag is digested by specific cellular enzymes that chop the damaged mitochondria into their constituent building blocks, such as amino acids. These building blocks can be recycled to build new mitochondria, similar to tearing an old building down and reusing the bricks to build a new structure. They can also be “incinerated” by healthy mitochondria and converted into energy. 

Energy, Health and Longevity
The low-calorie-diet induced activation of this cellular garbage disposal machinery may, at least partially, explain the known health benefits of caloric restriction. Research, linking caloric restriction to prevention of age-associated neurological disease as well as issues like wrinkled skin and energy decline, supports CR’s role in promoting cellular health.

Removing damaged mitochondria simply makes biological sense for two reasons. First, as already noted, cleaning house makes room for new mitochondria. Second, it helps maintain energy balance, commonly referred to as homeostasis, bringing the energy level of the cell from a deficient to a sufficient state.

In short, the machinery necessary for maintaining a cell free of damaged components is critical to the health and longevity of the organism.

Other Cellular Help

But is caloric restriction the only way to stimulate cellular housecleaning? A plethora of research has actually identified a compound with similar effects. Initially isolated from red wine, and later from other plant-derived extracts, this substance is resveratrol. It, too, has been shown, in cellular studies, to activate the SIRT1 enzyme.

Currently, there is also at least one study demonstrating resveratrol to be a potentially effective agent in certain models related to age-associated neurological health. To date, the results from these preliminary studies of the effects of the compound on animal and cell cultures are encouraging. (See November 2007 Juvenon Health Journal, "Resveratrol Continued: Promoting Energy Balance, Disease Resistance"). Whether these results will translate into an effective solution for promoting human health remains to be determined.

Since the 1930s, caloric restriction (CR) has been credited with both improving the health of animals and significantly increasing their life span. Recently, researchers at the National Institutes of Health in Bethesda, MD, and Harvard University Medical School and Brigham and Women’s Hospital in Boston, MA, conducted a study that demonstrated at least one of the mechanisms involved in producing CR’s well-known health benefits.

The experiments, discussed in the March 2008 issue of Proceedings of the National Academy of Science, focused on one of the key cellular enzymes activated by a calorie-restricted diet, SIRT1. In previous investigations, this enzyme has been shown to have numerous effects on biochemical pathways, some of which are widely held to be the basis for CR’s life-extending properties. The subject of this “Research Update” demonstrated, for the first time, a new CR function: the activation of the cellular machinery necessary to remove old, worn-out or damaged cellular structures.

This housecleaning process, known as autophagy (self-digestion), is critical to cellular health as it makes space for new, active cellular structures to replace old, damaged material. Impaired autophagy has been linked to disease, especially age-associated illnesses affecting the nervous system, such as Alzheimer’s and Parkinson’s disease. Furthermore, a clear association has been demonstrated between a general decline in the age and health of an animal and the activity of the autophagic cellular machinery.

Click here to read the full abstract.
"A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy"
PNAS | March 4, 2008 | vol. 105 |
no. 9 | 3374-3379

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:  Does Juvenon stimulate cell division?   — J.

ANSWER: There is no experimental evidence to indicate the active components in Juvenon have a significant effect on cell division. However, the components have been shown to improve cellular health and the health of the energy-producing cellular structures known as mitochondria.

Send your questions to AskBen@juvenon.com.
For more questions and answers, go to juvenon.com/product/qa.htm.

Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon's Scientific Advisory Board.