March 6, 2007
The chemist examined the role of activated oxygen molecules in biological processes.
We challenged experts across fields to imagine a new way to solve the problems of human aging. Our question: What if Humans were Designed to Last? By S. Jay Olshansky, Robert N. Butler, and Bruce A. Carnes Illustrations by Thom Graves When Michelangelo painted The Creation of Adam on the ceiling of the Sistine Chapel, he portrayed the Renaissance view of humanity as having been molded by the hand of its creator, a "perfect"
March 1, 2007|
By S. Jay Olshansky, Robert N. Butler,
and Bruce A. Carnes
Illustrations by Thom Graves
When Michelangelo painted The Creation of Adam on the ceiling of the Sistine Chapel, he portrayed the Renaissance view of humanity as having been molded by the hand of its creator, a "perfect" physical specimen. Charles Darwin, when drafting his theory of evolution, presented imperfections in humans' anatomic structures and functions as the strongest evidence for his theory. It now appears they were both right.
A coordinated network of molecular processes providing cells with nearly flawless surveillance, maintenance, and repair capabilities exemplifies the "perfection" of the human body. Living things need this precision in order to survive to reproductive maturity in the face of a hostile environment and the toxic debris that the cellular machinery of life generates. Meanwhile, subtle changes and imperfections at every level of biological organization give rise to the diseases and disorders associated with aging and impose limits on the duration of life, but ultimately, these changes and imperfections drive the evolutionary process itself. The juxtaposition of Michelangelo's perfection and Darwin's flaws embodies the linked stories of reproduction and death.
Evolution has given humans a beautifully orchestrated set of genetic programs to carry most of us through to sexual maturity, but we have also been given a brain large enough to ponder our demise. Yet, if the molecular, cellular, and genetic machinery used to conceive, develop, and operate a human were designed rather than the result of evolution, humans would be different and life would look different. This is our challenge. We asked experts in gerontology, neuroscience, genetics, cell biology, development, and health and fitness science to devise a human that would stand the test of time. Here's what they've come up with.
In the absence of planned form and designed function, what we have is a living machine that appears well thought out, but which fails when operated beyond its biological warranty period. Some anatomic fixes could make a difference in aging populations: Most men older than age 50 can attest that the prostate gland has the functional plan of an apprentice's first effort rather than the end result of intelligent design. Anyone who understands how time takes its toll on the body and mind, however, will recognize that designing a human body built to last requires far more substantive changes than meddling with simple anatomy.
So we've asked our experts to fiddle with physiology and tinker with the inner mechanics of life at its most basic biologic level. Although it is inevitable, for now, that all systems in the body experience some level of functional decline with the passage of time, not all components of the body degrade at the same rate. Furthermore, some structures are more vulnerable than others.
Particularly troublesome are two kinds of cells in the body that generally stop replicating past the stage of growth and development - neurons and muscle fibers. Two of our expert fixes deal with these problems specifically. John Q. Trojanowski, professor at the University of Pennsylvania, and director of the Institute on Aging and the Alzheimer's Disease Center suggests that the problems of neurodegenerative disease could be avoided if neurogenesis in the brain worked better, replacing spent neurons before they begin to cause problems for themselves and surrounding tissue.
Similarly, the nerve loss that may invariably lead to muscle loss in the body (sarcopenia) could be avoided with excess motoneurons, suggests Michael Bemben, professor of health and exercise science at the University of Oklahoma in Norman.
Some of the fixes strive to uncouple the links in our body's systems. The associations between endocrine function and bone formation invariably doom bone to deteriorate as hormone levels in the body decline. Other intriguing clues have shown us that senses such as taste and smell may influence the rate at which we age. Might parsing out these systems help us enjoy longer, more healthy lives?
Perhaps the best solutions would occur at a cellular or even a molecular level, increasing the quality and durability of life's most basic building blocks. Mopping up excess free radicals is a start. But even that covers only one theory as to the potential causes of aging. Leonard Hayflick, who demonstrated the finitude of repeated cell divisions so elegantly in the 1960s (see Foundations ) offers perhaps the most fantastic if most unattainable fix: Perfect or near perfect synthesis, maintenance, and repair of every biomolecule in the human body, he says, would make the risk for most age-related diseases and disorders simply vanish. Even this is not without tradeoffs, however. Such perfection would also wipe out those subtle changes and mistakes that made us what we are, tipping the scales in favor of Michelangelo.
Technologies are emerging that extend survival by delaying death from chronic fatal diseases. Pushing this envelope may briefly quench our insatiable thirst for extended life and temporarily quell our fear of death, but continuing to do so may turn out to be harmful unless it soon becomes possible to scientifically engineer an extension of the vigor of youth in both body and mind. In this article we go beyond usual scientific reasoning and imagine how the human body might have been designed differently if biology were goal-oriented. Meddling with such features is an inherently tricky business, but imaginative and innovative approaches to tackling the problems of an aging body is certainly worth encouraging.
Here, we imagine how the inner workings of the human body might have been designed differently, had a healthier and longer life been the motivating force that shaped life. Our goal is not to create new methods of combating disease, but rather, to spark an idea, trigger a thought, and inspire others to think outside the box by first imagining a new future of human health that is better than the present - and then working to make it so.
THE REJUVENATING BRAIN: The most troubling part about aging is our ability to contemplate it, and for this reason perhaps, the consequences to our brains are the most frightful. I study neurodegenerative disorders including Alzheimer, Parkinson, and frontotemporal dementias, which become more common with advancing age but are not always associated with age specifically. Many of these disorders are closely associated with filamentous aggregates, such as those containing amyloid, tau, and -synuclein. These aggregates quickly gum the normal physiology of neurons and often become cytotoxic.
The Fix: An improved system to fold proteins and destroy unwanted proteins could drastically reduce the propensity for aggregation. Perfecting the physiology of chaperone proteins and improving the efficiency of lysosomes, proteasomes, and all the enzymes that eliminate the accumulation of disease-causing proteins would significantly reduce the likelihood of these diseases occurring. However, this fix wouldn't address neurological damage resulting from head trauma or stroke. A simple, cell-for-cell replacement model of neurogenesis might provide a more elegant solution. If a cell dies, a population of adult neural stem cells would quickly replace it.
The Tradeoffs: One downside of improving regenerative capacity is that increased cell division to make more cells and replace those that degenerate could presumably spiral out of control and flip over to cancer. Moreover, the precise wiring of the brain is not something to be taken lightly. If neuroregeneration overcompensated only slightly, dysregulation of neuronal crosstalk could lead to conditions such as schizophrenia or seizure.
-John Q. Trojanowski, University of Pennsylvania
LONGER IN TOOTH: The deterioration and loss of teeth that comes with old age affects more than smiles; gum disease has been associated with increased risk for heart disease and might quicken the pace of aging. Poor nutrition after tooth loss could also cause problems. P. Holm-Pedersen of the University of Copenhagen has been presenting data on a 600-member aging cohort in Denmark, which shows a statistically significant association between tooth loss and the onset of disability, although the link is not necessarily causative.
The Fix: Stronger, more resilient enamel might stave off decay. A more elegant fix would entail a third set of teeth erupting at the age of 55.
The Tradeoffs: The tooth buds from a third set of teeth might necessitate a larger jaw. Having teeth erupt from the rear like those in elephants might solve this. However, many people past the age of 20 can recall intense pain when wisdom teeth erupt; constantly growing teeth, similar to those in horses, might address this.
-Bruce Carnes, University of Oklahoma, Health Sciences Center
THE PERFECT EYE: In addition to some well known engineering flubs in the eye, more than a quarter of individuals age 75 years and older report vision impairment even with corrective lenses. Cataracts and other damage caused by aging and a lifetime of exposure to incidental ultraviolet radiation account for more than half of all blindness.
The Fix: The tiny pink lumps in the inner corners of human eyes are the vestiges of a nictitating membrane - a third eyelid still functional in sharks, birds, and even some mammals. A similar sideways sweeping membrane, if translucent and able to block harmful rays, could provide additional protection when needed and be retracted in the dark.
The Tradeoffs: As skin ages - also due in no small part to the sun - it becomes loose and less flexible. Surgery to correct drooping eyelids (blepharoplasty) is already the third most popular plastic surgery, and adding a third lid would entail more surgery. For this reason, a simpler solution would be engineering a photochromic cornea. A biomolecule with the same properties as silver halide and other materials used in so-called Transitions lenses would darken in the presence of UV light and protect the lens and retina.
SENSELESS AGING: The effects of calorie restriction on longevity in several animal species are well documented. Increasingly, evidence suggests that sensory systems such as smell may have a similar effect. Last month, our group showed that the life-extending effects of dietary restriction in flies are partially reversed when the flies are exposed to excess food odorants. Knocking out the odor receptor Or83b resulted in life extension that was largely independent of dietary intake. Other studies in Caenorhabditis elegans have implicated scent and gustatory pathways in modulating aging, partly through insulin-dependant (i.e., daf-16) signaling pathways. Although more studies are needed, the implication is that perceptual systems may play a major role in informing the organism of its environment, and in so doing may trigger physiologic decisions that result in altered longevity.
The Fix: Short of deleting human senses, uncoupling them from the burden of our evolutionary past would be useful. Relevant odorants likely tap into adaptive hormonal pathways that have been honed by evolution to alter life-history patterns and maximize individual fitness - for example, to maximize reproductive effort at all costs when we perceive nutrient abundance. We may rewire these systems to enforce somatic endurance in response to common odors.
The Tradeoffs: The apparent interconnectedness between the senses and longevity-modulating pathways is perceived as "bad" only according to today's values. That doesn't mean they don't serve a useful purpose. Perhaps a more elegant solution would be to engineer the ability to switch between states - for example, to maximize reproductive capacity when starting a family, and to increase stress resistance when raising those children.
- Scott Pletcher, Baylor College of Medicine
TAKING THE BITE OUT OF CHOLESTEROL: The modern human diet is high in animal fat and processed foods. Excess low-density lipoprotein in the blood appears strongly linked to a process in which plaques form along arterial walls, causing narrowing and sometimes blocking of blood vessels. About half of all Americans exceed guideline levels for cholesterol. As an older population has become more commonplace, so too have heart disease, stroke, and all the attendant costs of a lifetime of plaque buildup.
The Fix: While enhancing the systems to reduce serum cholesterol levels seems attractive, the extra enzymatic activity required to process these lipids would likely necessitate a substantial size increase in what is already the body's largest internal organ, the liver. So, the best solution is a functional one: Coat the entire vascular system with a Teflon-like surface. Polytetrafluoroethylene is inert, has no net charge, and has the lowest friction coefficient of any known solid. A biomolecule with these properties, if expressed on the surface of endothelial cells lining the vasculature, would greatly reduce plaque buildup.
The Tradeoffs: An effective coating would have to be sufficiently breathable so that it doesn't inhibit the transfer of nutrients and oxygen. Moreover, arteries need to be elastic. The hardening effects of a polymer like Teflon could reduce pumping efficiency.
-P. Michael Conn, Oregon National Primate Research Center
BONE REGAINED: Osteoporosis, characterized by a decline in bone mass and a weakening of its micro-architecture, appears to be caused by an imbalance in bone remodeling. The three phases in the bone remodeling cycle - activation, resorption, and formation - involve different cells. Osteocytes activate the cycle in response to mechanical signals. Osteoclasts synthesize lysosomal enzymes that can degrade bone matrix components, resulting in the bone resorption phase. Hormones and local growth factors stimulate osteoblasts to produce collagen that forms the new matrix, completing the remodeling cycle. Bone loss occurs when resorption occurs faster than formation, a process that begins in humans in their early 30s.
The Fix: Age-related changes in endocrine function greatly affect bone mass and fracture risk. Decreasing the sensitivity of bone cells to systemic hormones might help. If bone cells could rely on their own intracellular signals for remodeling, a normal balance between resorption and formation would persist. The mechanism for the decreased sensitivity could be analogous to the decreased insulin sensitivity observed with aging. One could impose a decreased number of hormone receptors, such as parathyroid hormone (PTH) on the bone cells, or a change in the biological effect of the hormone-receptor interaction within the bone cells.
The Tradeoffs: Bone tissue functions as an important reservoir for calcium, but with a decreased number of PTH receptors, PTH would not be as effective in mobilizing calcium from the skeleton in response to lowered blood calcium levels. Moreover, it has been shown in animal models that the estrogen receptor mediates bone response to mechanical loading, suggesting that a decrease in estrogen receptors would decrease the bone response to weight-bearing exercise.
-Debra Bemben, University of Oklahoma
LIVING STRONGER LONGER: The loss of muscle mass associated with aging accounts for a decrease in basal metabolism and in muscular strength, which can lower physical activity levels, resulting in diminished postural reflex, a loss of balance, and an increased risk for falls. Sarcopenia is a multifaceted problem with two potential primary mechanisms. The problem might be myopathic in nature, but evidence also indicates that a loss of muscle innervation might cause sarcopenia. Strong evidence suggests a progressive loss of high-threshold motoneurons (those that innervate fast-twitch fibers) as demonstrated by the proportional loss of fast-twitch fiber numbers.
The Fix: If loss of neural innervation to the muscle fiber is the primary cause for the loss of muscle mass, then muscle fiber number could be maintained as long as neural integrity is stable. In the brain, it appears that humans have roughly four-fold neuronal redundancy. In most people, as many as 30% of the cerebral neurons are lost due to wear and tear of normal life, but far less than the approximately 80% reduction necessary to produce clinical symptoms. One way to ensure an adequate number of functioning motoneurons would be to build a similar redundancy into the anterior or ventral horns of the grey matter in the spinal cord.
The Tradeoffs: The extra space needed to 'house' these extra nerve cells within the spinal cord would necessitate an increase in size of the spinal cord and concomitant increase in the vertebral column, which could influence posture, balance, and gait. A second problem might be a greater incidence of peripheral nerve diseases such as shingles or systemic lupus with increased age.
-Michael G. Bemben, University of Oklahoma
UNFREE THE RADICALS: Metabolic free radicals are thought to be a significant cause of biomolecular damage. The accumulation over time of unrepaired damage caused by free radicals has been linked to a host of diseases and has been prominently implicated in the aging process itself.
The Fix: The solution to this problem must be systemic. While natural antioxidants are produced endogenously and occur in food, more powerful antioxidants also exist, such as amifostine (WR-2731), a radioprotector compound produced in the laboratory and used to ameliorate damage caused by radiation therapies. In addition, they tend to concentrate within the mitochondria where metabolic free radicals are produced, and they adhere to nuclear DNA. The latter attribute is significant: As it increases the structural stability of the DNA, it may also slow the cell cycle. If a gene to produce such compounds were introduced into the mitochondrial genome, the rate of aging should be slowed, and cancers should be reduced or delayed along with all other degenerative diseases that free radicals cause.
The Tradeoffs: Free radicals do participate in a number of important functions. Immune cells use free radicals to attack and destroy invaders and infected cells. Free radicals participate in the detoxification of harmful chemicals, and are involved in hormone production, enzyme activation, and mediation of cell signaling. Disrupting these important processes could easily jeopardize the health of the individual. So, a more powerful endogenous antioxidant system would have to be finely tuned.
The best solutions might occur at a cellular or even molecular level.
STOP AGING AT THE MOLECULAR LEVEL: Theories to explain the finitude of life are based either on a purposeful genetic program like that for biological development, or on the occurrence of random events that produce errors in essential biomolecules. It is now believed that genetics governs longevity but that random events produce age changes. Age changes result from the increase in molecular disorder that, after reproductive maturation, slowly begins to exceed the capacity for repair, turnover, and synthesis of biomolecules. The very systems that are engaged in repair, turnover, and syntheses are themselves subject to randomly accumulating errors.
The Fix: Developing a perfect human being, built to live a life that is longer and healthier than what is experienced now, would simply require that all processes designed to maintain, turn over, or repair proteins, lipids, carbohydrates, or nucleic acids be carried out with near-perfect fidelity. With this ability in place, age changes and the consequent vulnerability to age-related pathology would decrease to the vanishing point.
The Tradeoffs: Beyond the ethical implications of creating such long-living beings with no reasonable exit strategy, we would be deleting a rich and fundamental source of biological diversity. Mistakes in the synthetic and repair machineries of the cell have created us as we are today. Turning off the power of this engine for evolutionary change would put us at a great disadvantage in adapting to new challenges and environments and leave us at a biological dead end.
-Leonard Hayflick, University of California, San Francisco
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