iAge: The Preservation of Human Energy through Aging

E = MC²

Einstein’s iconic formula defines the theory of relativity. We think of this formula mainly in quantum physics and space exploration, but it also applies to our body. The theory specifies that a body that weighs say 68kg (150 lbs.) will have 6,111,535,215,410,359,952 Joules of energy. This is 6,111 Petajoules (PJ) which translates to 1,697,500 giga watt hour. In comparison, 31.5 PJ is the electrical annual output of a large power plant, while 210 PJ is equivalent to about 50 megatons of TNT. This is the amount of energy released by thirty Tsar Bomba, the largest man-made nuclear explosion ever.

One person is a walking universe of restrained energy. We can only access a small percentage of this energy so most of this energy remains inaccessible. But our biology knows how to utilize part of this energy. And one way that it uses energy is by storing it in fat. It is a reserve that our biology does very well. This balance is based on the first law of thermodynamics applied to an open system. It is an open system because energy can be added to the system by ingesting food. Energy that is not used by the body is stored in the form of glycogen, lipids (mainly in the form of fatty acids), and protein. Unlike glucose, fat can be stored in large quantities for extended lengths of time. As a result, fat mass is the main long-term energy storage mechanism of the human body.

Surprisingly, we are built with two systems of energy: glucose and ketones. In ketosis, once we run-out of glucose, we switch to our fat for energy. We break down fat into fatty acids, and those fatty acids which the liver transforms into ketones, which are then used as the energy source by the brain, muscles, and other tissues. Ketosis occurs through high fat intake, fasting, or reduction of carbohydrates.

The average adult has as much energy stored in fat as a one-ton battery. Fat is a very good system when there is energy shortage, but becomes problematic when there is an abundance of food since the body is excellent at storing fat. Especially since the body protects any loss of fat. Weigle et al (1988) reported that the body is aware of how much energy is stored. So for someone who lost a lot of stored energy (say after dieting) the body uses 18% less daily energy than those of the same relative body weight conducting the same activity, as those who had never dieted. This is a clever energy conservation system that we see in action better in older age.

The average human, at rest, produces around 100 watts of power. This equates to around 2000 kcal (kilocalorie =4184 joules) of food energy, which is why your recommended daily intake of calories is around 2000 kcal. Over periods of a few minutes (or a few hours in the case of trained athletes), we can comfortably burn 300-400 watts of energy—and in the case of very short bursts of energy, such as sprinting, some humans can output up to 2,000 watts.

As we get older this equation changes dramatically. We become less efficient. The idea that aging is simply an attrition of energy is one of the oldest theories in gerontology starting with Aristotle (384-322 BC) and was later adopted by the Romans, Muslims and Western European medical establishments. It became the basis for our early understanding of how the human body works. Essentially, Aristotle held that the human body was filled with four humors: black bile, yellow bile, phlegm, and blood. Any imbalance in these four humors resulted in diseases and disabilities. Aging is caused by the drying out and cooling of these humors. This idea had a wide following, and involved numerous hot baths and saunas in order to maintain our wetness and heat.

Surprisingly, older adults do have slightly lower temperatures. The 98.6° F benchmark for body temperature comes from Carl Wunderlich—a 19th-century German physician—is not accurate for older adults. In 2005, Irving Gomolin from Winthrop University Hospital in New York, found that older people have lower temperatures than younger adults. In a study of 150 older people with an average age of 80-plus, they found an average temperature of 97.7°. What is fascinating is longer you survive the lower your body temperature…or is it the other way round? Although most have seen lower temperature as correlated with mortality, lower temperature might be a protective function, knowing that the body likes to conserve energy. And that is exactly what a 2006 research study found. An Italian researcher Bruno Conti at the Scripps Research Institute showed that a decline in body temperature is beneficial. The study found that mice that had lower core body temperatures lived 12% (male) to 20% (female) longer than mice with higher core body temperatures. The difference in temperatures between "cold" and "normal" mice was 0.5-0.9 F (0.3-0.5 C), which is the same difference between the average young person and the average older adult. Perhaps the body is conserving energy by reducing its operating temperature and therefore reducing metabolic rate, free radicals and stress on the system.

The science behind this anomaly is just now becoming clear. One of the known ways to increase longevity is to restrict calorie intake—eating fewer calories. Caloric restriction increases lifespan in all sorts of animals. Several studies have reported that animals on reduced calorie diets also had a lowering of core body temperature. By conserving energy and reducing temperature, our body is also slowing the aging process. One interpretation from this is that the reason older adults may have lower body temperature is not because they are dying, but because it is our body’s way of preserving energy, resulting in living longer. In the Baltimore Longitudinal Study of Aging, men with a core body temperature below the average (median) lived significantly longer than men with body temperature above the average. But how does Caloric Restriction (CR) result in lower temperature and conserving of energy?

After Caloric Restriction (CR) was initially discovered in 1935 in mice, it has been tested with varied organisms and it has been shown to increase the lifespan in yeast, insect, and in non-human primates. In humans CR is still undergoing testing, although initial results suggest prolongation of life as well as prevention of age-related diseases are likely outcomes. The mechanism seems to emulate the genetic work of life prolongation, in that the CR elicits a hormesis event—a low level stressor that stimulates a positive response. The system is believed to involve genes that become active when stress occurs. These genes are referred to as epigenetic. Epigenetics are genes once thought to be “junk” genes, but now we are finding that they can be switched on or off. In most cases they are triggered by environmental factors. The best way to study the effect of genetics on longevity is to look at twins. Monozygotic twins, those that split from a single egg, have nearly similar genetic makeup at birth. In contrast, twins that have a different egg (dizygotic) only share the same level of genotype as with any other siblings.

More than three decades ago, Cook and his associates published a study looking at the onset of dementia among monozygotic twins who were both affected by Alzheimer's dementia. In one case study, dementia began in her late 60s, while in the other twin the onset of dementia was at age 83. Subsequent studies confirm that although monozygotic twins might both have the disease, how they express them and when they express the disease might differ. The difference was used attributed to the environment. In support of this interpretation recent studies are blurring the difference between genetics and the environment. In 2000 biologists Randy Jirtle and Robert Waterlanda from Duke University modified the expression of a gene—called agouti gene--which made mice fat, yellow and prone to cancer and diabetes. These mice did not live very long. After an intervention however, these researchers produced young mice that were slender and healthy, evading their parents' susceptibility to cancer and diabetes living to an active old age. The researchers virtually erased the effect of the agouti gene. Remarkably, the researchers modified the expression of this gene not by altering the mice genes, but by changing the moms' diet. Feeding the mother a diet rich in onions, garlic, beets, and in food supplements often given to pregnant women the researchers provided a chemical switch that reduced the agouti gene's harmful effects.

These foods—known as methyl donors, folic rich foods—enhance or diminish gene activation and gave birth to a whole new science of epigenetics.

The same changes in our genetic expression are seen throughout our life. With older adults expressing more variance in their genetic expression. In 2012, Jordana Bell of King's College London and colleagues looked at the genes of 86 sets of twin sisters aged 32 to 80, and repeated with another 44 sets of younger twins aged 22 to 61, and discovered that 490 genes linked with ageing showed signs of epigenetic change. In particular, among this epigenetic expression were four genes that relate to cholesterol, lung function and maternal longevity. What is phenomenally interesting is that these changes are not just brought about by diet and methyl rich donors, but also by such lifestyle factors such as smoking, environmental pollution, stresses, and attitude.

There are many studies in this area of how genetic manipulation changes longevity through the conservation of energy. The three seminal research studies all have one thing in common and it is to do with how the body reserves energy through growth hormones. The first type is a classic experiment by Michael Rose who began manipulating the life spans of fruit flies by allowing them to reproduce only at late ages. The subsequent progeny of flies evolved longer life spans and greater reproduction over the next dozen generations. If our parents delayed producing us, then our body seems to know to conserve energy in order to make the body live longer to enable it to pass on its genes at this delayed period.

The second type of experiment uses examples from nature, which were then emulated in the laboratory at U.C San Francisco by Cynthia Kenyon. Here they chemically knocked out certain genes in flatworms, the gene daf-2 which partially disables receptors that are sensitive to two hormones—insulin and a growth hormone called IGF-1. This had the effect of nearly doubling the flatworms’ lifespan. These long-lived worms looked and acted younger than their control group, implying that extending the lifespan also extends healthy life. By conserving energy by weakening insulin and a growth hormone, the flatworms lived longer.

Then there is the third type of genetic observation with mice, in particular the work done by Richard Miller, and his infamous mouse called Yoda (who is now deceased.) Like other dwarf mice, Yoda had a natural genetic mutation that obstructs the production of growth and thyroid hormones. Dwarf mice tend to grow to only about a third the size of normal mice, which helps them live about 40 percent longer. The common denominator in all these experiments and observations is that stunted growth and a conservation of energy correlates with increased lifespan. Surprisingly there are two inclusive and complimentary theories that can explain these findings.

The theory of Antagonistic Pleiotropy argues that some genes have contradictory effects at different age. Genes which might enhance your reproductive success at a younger period in our life—genes that increase testosterone in men, resulting in more muscle mass and masculine secondary sexual characteristics—may at an older age have detrimental effects on survival later in life—in the testosterone example it is the elevated risk of cancer. Natural selection tends to favor these kinds of genes because they maximize fitness and the passing of genes while the higher mortality occurs in post-reproduction stage will have little impact on increasing the number of offspring. The second theory is that of Disposable Soma which states that given that there are finite resources to maintain and repair cells and organs, the body conserves energy and protects itself just long enough so that we are able to pass on our genes.

As with all genetic work there are many confounders. There is no direct translation from the genotype to the phenotype. The environment can intervene as is being shown with epigenetics. Even if we accept that stunted growth might preserve energy and improve lifespan, other factors might negate such gains. And that is the case with a southern Ecuador group where more than 250 individuals are thought to have Laron syndrome—IGF-1 deficiency in primary growth hormone—caused by a mutation in the growth hormone receptor gene with affected individuals growing to less than 4 feet tall. Although Laron patients appear to be protected against developing cancer, this apparent protection does not translate to a longer lifespan due to trauma and alcoholism. There is a schism between lifespan and theoretical lifespan…human behavior. The ability of the body to preserve energy might be negated by our negative behavior.

Tuesday, December 15, 2015

The Preservation of Human Energy through Aging

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