Pathways of AgingJanuary 2004
Science has not yet found a way to keep us young forever. But there is good news! The latest research on aging reveals that, though we cannot actually stop the ravages of time, we may be able to slow them down.
Experts now know that it is not simply inherited genetics that determines who will live the longest in an energetic, disease-free state. By the time humans reach the age of 80, behavioral choices become significant determinants of a person’s overall health and longevity.1
The article you are about to read examines the mechanisms behind growing old and explains new ways in which aging humans can slow this devastating process.
There is no single cause of growing old, but the various mechanisms that characterize aging are often interrelated. The good news is that scientists are identifying many of these interrelated pathways of aging. This provides those of us alive today with an unprecedented opportunity to gain at least partial control over this devastating process.
For the past 20 years, scientists have focused on free radicals as a culprit in the development of age-related diseases. New research provides a basis that links free radicals with other pathological changes that cause cellular malfunction or mutation (i.e., cancer).
As we age, the body generates higher levels of free radicals and other oxidants.2 Unfortunately, antioxidant defenses do not generally rise to meet this challenge,3 remaining either constant or in some cases declining. For example, cells generate more of the oxidants superoxide and hydrogen peroxide, while levels of the key cellular antioxidant glutathione decline progressively with age.4
Studies show that the life spans of animal species are affected by their levels of oxidant generation. The higher the level of oxidant generation in a species, the shorter will be its average life span. When scientists engineer cells of Drosophila (fruit flies) to increase production of the antioxidants superoxide dismutase (which quenches the superoxide radical) and catalase (which neutralizes hydrogen peroxide), the flies live longer and their metabolic potential increases.
How Free Radicals Deplete Cellular Energy
Scientists have identified age-related decreases in three enzymes that regulate both oxidation and cellular energy production (cellular respiration). These enzymes—cytochrome c oxidase, NADH dehydrogenase, and succinate dehydrogenase—regulate three of the five steps in the process by which cells oxidize food to generate energy in tiny organelles called the mitochondria. The age-related decreases in the activity of these enzymes, which occur in a wide variety of mammalian species including humans,5 are believed to play a role in age-related increases in oxidation.
In a fascinating study on rats, supplementation with acetyl-L-carnitine restored cytochrome c oxidase to the level seen in young animals.6 This same study showed that acetyl-L-carnitine treatment rejuvenated an important component (cardiolipin) of the mitochondrial membrane that resulted in the restoration of cytochrome c oxidase activity.
Cellular energy generation in the mitochondria is both a key source and key target of oxidative stress in the cell. One can therefore envision a model whereby the inevitable increased production of free radicals compromises mitochondrial efficiency, and eventually energy output, in a detrimental feedback loop.7 Yet supplementation with acetyl-L-carnitine enhances mitochondrial membrane efficiency by restoring a critical antioxidant enzyme (cytochrome c oxidase) to youthful levels.
Lethal Consequences of Cellular Energy Deficit
Scientists long ago discovered that acetyl-L-carnitine and coenzyme Q10 help protect against cellular energy deficits by maintaining healthy mitochondrial function. With new evidence showing a vicious cycle of cellular energy depletion causing more damaging free radicals, and the increased free radicals then causing more cellular energy depletion, the importance of nutrients that boost endogenous antioxidants such as alpha lipoic acid becomes much more apparent. Alpha lipoic acid increases glutathione levels within our cells.
Protein Degradation Initiated by Free Radicals
Protein carbonylation increases with age, damaging about one-third of the body’s proteins later in life.10,12 These dysfunctional proteins accumulate in vital organs, clogging the cellular machinery just as the buildup of sludge clogs an automobile engine until it seizes. Carbonylated proteins are visible in aging skin and cataracts. Their destructive effects on cellular function underlie diverse age-related conditions, from neurodegeneration, cardiovascular disease, and kidney failure to the chromosomal instability that leads to cancer.
New research shows that as yeast cells age through succeeding cell divisions, a threshold is crossed that dramatically increases chromosomal instability, thereby increasing genetic defects by a multiple of 40 to 200.13 Chromosomal instability is a prerequisite for tumor development and increasingly is recognized as a driver of age-related degeneration. The authors of the yeast study point out that mutation rates increase with age, while the risk of developing cancer increases more than tenfold in humans from age 40 to age 70. They postulate that the accumulation of age-related damaged proteins thwarts the cell’s sensors for detecting DNA damage. Thus damaged proteins prevent cells from repairing damaged DNA or activating an orderly cell-death program. Consequently, damaged cells survive and reproduce, leading to mounting genetic, and in particular chromosomal, instability.
Copper Damages Brain Cells
Glycation Harms Arteries, Eyes, and Kidneys
The best ways to protect against protein degradation, copper-zinc brain toxicity, and chromosomal instability will be discussed later in this article.
The “Sugar” Connection
According to the American Diabetes Association, diabetes affects about 17 million Americans. Some medical professionals believe this figure may vastly underestimate the true scope of the pandemic. An additional 16 million are suspected of having a precursor condition known as prediabetes.18 When prediabetic patients are accounted for, the legions of people at risk of developing serious diabetic complications swell alarmingly. Taken together, known diabetics and prediabetics—collectively described as having “glucose-handling” difficulties—represent a shocking 12% of the entire US population. Alarmingly, diabetes was listed as the sixth-leading cause of death on death certificates in 1999, and records suggest that this figure may grossly underestimate diabetes’ actual contribution to deaths. And the statistics are not improving. To the contrary, the ranks of diabetics are swelling along with our collective girth.
The Insidious Progression of Diabetes
Our understanding of type II diabetes and its related disorders, such as impaired glucose tolerance and impaired fasting glucose, is undergoing a radical change, particularly as data suggest that the risk of complications commences many years before the onset of clinical diabetes.19,20
Type II diabetes was previously regarded as a relatively distinct entity. Doctors waited until fasting blood glucose levels were consistently above 126 mg/dL before taking steps to reduce the excess glucose. Little else was done to address the multiple complications associated with the diabetic state.
We now know that the impaired ability to efficiently handle glucose, progressing all the way to full-blown type II diabetes, is often a manifestation of a much broader underlying disorder.21 This includes the metabolic syndrome (sometimes called Syndrome X), a cluster of cardiovascular risk factors that includes visceral obesity, increased propensity of blood to abnormally coagulate, and loss of protein in the urine, in addition to impaired glucose tolerance.