Home / Juvenon Health Journal / Healthier Aging: Clues from the Youthful Liver of an Aging Mouse 8/08


Juvenon Health Journal volume 7 number 8 august 2008

healthier aging: clues from the youthful liver of an aging mouseBy Benjamin V. Treadwell, Ph.D.

Oh those painful joints, aching muscles and wrinkled skin. Not to mention the loss of energy and mental acuity. Of course, I’m describing physiological symptoms that many of us complain of as we get older. The age of onset and the intensity vary from person to person. But almost all of us do experience gradual deterioration of our bodies. Why?

Over the years, a number of theories have been floated. Many seem to have merit, with at least some scientific evidence Recent information may help unify some theories on how and why we age.supporting them. To date, none have been proven. However, some recent, exciting information may help unify several current theories on how and why we age.

Cleaning Cellular House
Our organs (liver, skin, pancreas, brain, heart, etc.) are composed of billions of specialized cells. To maintain a healthy, metabolically balanced organ, each cell must carry out numerous activities that require a significant amount of energy. The energy, of course, is derived from the food we consume…but not always.

In prolonged starvation, the body uses damaged cellular parts for energy.Under certain conditions, we utilize (cannibalize) parts of our own body for energy. In fact, during prolonged starvation, the body will first dismantle damaged cellular structures and use the pieces for energy. Think of it as chopping up the old, worn-out furniture for fuel to heat the house when the wood supply has run out. The result is a cleaner house/cell, which now has space for brand new furniture/structures.

Caloric restriction (consuming only enough calories per day to maintain a healthy minimal weight), along with exercise, also appears to activate the specialized machinery involved in removing the old “cellular furniture.” The net effect? Healthier organs for a healthier animal.

Biochemical Garbage Disposal
The majority of our cells have at least four distinct biochemical pathways for removing damaged or worn-out proteins, lipids and mitochondria. Each of the four specializes in a particular type of clean-up work, although it appears that, if one pathway is overloaded, one or more of the other three is activated to help out.

For the large jobs, such as removing oxidized or damaged mitochondria, the cell relies on Macro-Autophagy. The damaged mitochondria are enveloped by a membrane that is then fused to the outer membrane of the lysosome, another bag-like cellular structure. The lysosome contains potent acidic digestive enzymes that enter the inner envelope to break down the contents into metabolites, readily used by the cell either forChaperone-mediated autophagy (CMA) removes damaged proteins. building new structures or for fuel to produce energy.

Another pathway, referred to as chaperone-mediated autophagy (CMA), removes smaller structures, such as damaged proteins. A specialized molecule in the cell, hsc70, recognizes and binds to the damaged protein, subsequently acting as a chaperone in ferrying it to the lysosome. The damaged protein-chaperone attaches (docks) to a specific receptor on the lysosome membrane, LAMP-2A (lysosome-associated membrane protein). It is then transported into the lysosome and digested.

Genetic Pathway Rejuvenation
A fascinating animal study recently demonstrated how the CMA pathway in the liver becomes sluggish as an animal gets older. This may, at least partly, explain the age-associated decline in liver function.

The research showed that liver function failure coincides with a loss of the liver receptor protein, LAMP-2A, and that this loss is considerable in a middle-aged (nine-month-old) mouse. The investigators found that, if they replenished LAMP-2A by inserting the gene responsible for its production into the mouse and activating it at six months of age, the animal’s liver remained as healthy as a youthful liver.

When the team examined the other three clean-up (garbage-disposal) pathways, they also appeared to be more active. Did rejuvenating the CMA biochemical pathway reduce the workload on the other pathways, improving their function? Would this, in turn, minimize the age-associated decline in other organ and cellular function?

A Man or a Mouse
The liver study seems to link the aging process to the cellular machinery necessary for removing accumulated cellular garbage. In other words, at least part of the reason the organs of our body age is because one or more of the four biochemical pathways for removing damaged or worn-out proteins, lipids and mitochondria begins to malfunction.

Other research groups have also reported an association between certain health problems – diabetes, neurodegenerative conditions such as Alzheimer’s, Parkinson’s, etc. – and impaired cell house-cleaning machinery.
A healthy, calorie-restricted diet may help improve cellular disposal activity.
This experimental data suggests that a healthy, calorie-restricted diet (with just enough food to maintain healthy weight), combined with regular exercise, may help improve the activity of the cellular disposal systems, and consequently the health of the individual. There are phytochemicals, such as the plant-derived resveratrol, which, preliminary research suggests, may mimic caloric restriction and may also help improve the health/function of the cell disposal systems. More research will tell.



Research Update

A group of investigators, led by Ana Maria Cuervo from the Albert Einstein College of Medicine, Bronx, NY, detailed some break-through findings on aging and organ failure in their article, “Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age,” published in the Journal of Cell Science. For the first time, investigators demonstrated ‘in vivo’ the relationship between the decline in the activity of a cellular cleaning system and age-associated accumulation of intracellular damage.

With age, the chaperone-mediated autophagy (CMA) system loses its capacity to remove misfolded and oxidized proteins from the cell, resulting in cell toxicity and gradual organ failure. The research, focusing on the liver, showed that this loss in CMA activity paralleled a loss of a key receptor protein, LAMP-2A, present on the membrane of the lysosome. This receptor is necessary for the docking, and subsequent digestion, of chaperoned damaged protein.

Using transgenic mice, carrying a gene coding for the LAMP-2A protein, the investigators demonstrated that turning the gene on just before the animals begin to show signs of aging resulted in the production of increased amounts of LAMP-2A on the lysosomal membrane. With the increase in LAMP-2A, there was no decline in CMA activity or corresponding loss of liver function.

The results of this study seem to generally link the cellular machinery required to remove damaged cellular components with the health of an animal. Failure of this system with age appears to precede organ failure and related physiological symptoms.

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.

Ask Ben
Dr. Treadwell answers your questions about Juvenon™ Cellular Health Supplement

question: I am 50 years old, healthy, and a loyal Juvenon user who feels good using it. Recently, I received information about stimulation of human growth hormone with a product containing natural ingredients. It is supposed to stimulate the pituitary gland. Do you think this product might cause cancer in somebody, like me, with a family history of cancer? Is this product something that I should be very careful about? I fear that it may promote growth of both bad and good cells. Let me know your opinion please. Thank you.  – L 

answer: I am not familiar with the specific product you mention and its claim to stimulate the pituitary to produce growth hormone. But I do agree with your cautious approach. Any substance put into our body that stimulates growth hormone activity may be dangerous as it could promote cancer cell growth. Although there are specific medical issues for which growth hormone or growth hormone-stimulating products may be helpful, they should only be taken with the recommendation of a qualified health professional.

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

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