Why We Age - Anti-aging and Life Extension

Definition of Calorie Restriction 

Calorie restriction (CR) is the practice of limiting dietary energy intake in the hope that it will improve health and retard the processes associated with aging. Typically reducing an animal’s calorie intake by 30 to 40% of what is usual for that particular species, whilst maintaining a proper level of nutrition results in an increase in general vigour together with an increase in longevity.  Note that this reduction in calorie intake includes a reduction in carbohydrate, fats and protein.  This increase in life expectancy and general health for calorie restricted animals has been seen in a wide variety of experiments conducted in a number of organisms.  These include rotifers, yeast, worms, spiders, fish, mice and rats.  Experiments are currently being conducted with primates to see if restricting caloric intake increases life expectancy with these animals also.  These experiments are already showing very positive results.

In human subjects, calorie restriction has been shown to lower cholesterol and blood pressure. Many researchers consider these to be the biomarkers of aging.  After all, there does seem to be a correlation between these conditions and likelihood of developing many diseases associated with aging. With the notable exception of houseflies, animal’s subjected to calorie restriction in a controlled and nutritionally balanced setting have shown an increase in longevity.  In order to differentiate between calorie restriction and simple starvation, calorie restriction is sometimes referred to by a variety of other names.  These include CRON or CRAN (calorie restriction with optimal/adequate nutrition) and CRL (calorie restriction for longevity).

General effects of Calorie Restriction

Experiments involving placing organisms on a calorie restricted diet have shown the below positive results:

• An increase in maximum and in average life expectancy
• An increase in general health
• A lower susceptibility to cancer
• Less likelihood of developing Diabetes
• Less likelihood of developing Kidney disease
• A reduction in the incidence of autoimmune disease
• A forestalling of the onset of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s

On a negative note, there has been an observed loss of fertility in experimental subjects.

Why does calorie restriction have such profound effects?

One question that is raised by many people upon hearing about calorie restriction is:

‘Why did such a mechanism evolve in the first place?’

A very valid question I would say.  One possible reason for the evolution of calorie restriction is that it was selected for in order that organisms could survive during boom/bust cycles.  If sources of food are scarce due to a draught or extremes of weather, then an animal cannot affectively reproduce.  In females there would not be enough food to sustain the reproductive process and even if offspring was produced successfully, it would be difficult for it to survive and develop to maturity.  Therefore during these times of scarcity, an organism’s fertility is not needed and is therefore selected against.  At the same time in order for an animal to still affectively pass on its genes to the next generation, the ability to endure this period of hard times is selected for.  The result of which, has been the evolution of a mechanism whereby low caloric intake triggers the body to become more efficient at protecting itself against damage and disease.  The calorie restricted organism therefore is a more vigorous and longer lived animal.

This is however just one theory on why calorie restriction is such an affective mechanism for retarding aging.  The exact mechanism by which it works is still unclear.  The difficulty with understanding calorie restriction is due to its multiple effects on the systems of the body.  From neuroendocrine, apoptotic to general metabolic changes all exhibited differently among specific organ systems, this diet has profound and complex effects throughout the bodies of vastly different organisms.

Why do animals age?

Evolutionary biologists have suggested a number of reasons for why organisms age in the first place.  It has been observed many times that an animal seems to be healthy and vibrant through the majority of its reproductive years.  Once an animal gets to the age where it is no longer reproductively active however, it seems to become rapidly more susceptible to degenerative diseases and ages rapidly.  One reason for this may be that natural selection lacks the ability to remove undesirable characteristics from the post reproductive period of life.

Natural selection works by a process whereby a stronger, fitter, faster or more intelligent animal is more likely to survive long enough to mate and to therefore pass its more potent genes on to the next generation.  A weaker animal is less likely to survive long enough to do so.  The result of this is that these stronger genes are selected for.  The weaker genes are however selected against.  In nature however, disease, predation, famine and draught are so widespread that an animal is statistically unlikely to survive past a certain period of time, regardless of how capable it is to repair cellular damage and fight off common infections.  Genes are therefore only passed on by these relatively young creatures.  Traits are then only selected for in order to allow an animal to function until that natural time when probability will ensure that a creature is unlikely to survive.  This means that in the unlikely event that a creature does survive past this reproductively active period, it will not possess the mechanism’s required in order to continue effectively repairing its body and fighting off infection.  Eventually this results in a general deterioration of all of the systems of the animal, leading to death.

How does Calorie Restriction slow down aging?

There are a number of theories that attempt to explain (at a molecular level) why calorie restriction retards the processes involved in aging.  At the route of aging is damage to the cells (of one form or another).  Damage that accumulates throughout the lifetime of an organism.  This damage eventually results in an animal losing its ability to sustain life.  Calorie restriction slows down the accumulation of this cellular damage. How it does so is however open to some debate.  Here are three of the theories that have been proposed to explain calorie restriction:

• It has been shown that oxidative damage to cells is reduced in calorie restriction experiments (Lee and Yu 1990).  A reduction in oxygen containing radicals (known as ROS molecules) such as superoxide and hydroxyl groups would occur if the metabolism was to slow down.  Experiments into metabolic level and calorie restriction (McCarter et al 1985) do not however show this to be the case.  In yeast and worms for example calorie restriction both speeds up and alters metabolism. The reason for reduced oxidative damage could however be more subtle in nature.  Perhaps a more efficient transportation of electrons through the respiratory chain of the cells mitochondria might reduce the production of ROS and therefore slow down this oxidative damage (Weindruch et al 1986).  Alternatively it could simply be that calorie restriction provides an organism with an increased ability to detoxify ROS.  This is supported by the fact that calorie restricted rats tend to be more resistant to treatment with oxidative agents (Semsei et al.  1989).  Evidence however in this matter is still inconclusive and conflicting results have been produced (Hauck and Bartke 2000).
• One theory that has been proposed and which is gaining some credibility is that calorie restriction increases the turnover of protein and therefore prevents proteins from accumulating damage.  Studies have shown that damaged and potentially harmful proteins do accumulate in the body as we age (Lavie et al 1982, Gracy et al 1985).  As fat levels reduce during calorie restriction, this could trigger a corresponding degradation of proteins, resulting in an increase of protein turnover.  It has indeed been shown that age-associated accumulation of oxidised proteins is actually reduced by calorie restriction (Aksenova et al 1998).  Also analyses of mouse skeletal muscle following a regime of calorie restriction (Lee et al 1990) showed an increase in protein synthesis and degradation.
•  As we age, the rate at which proteins become modified covalently by reactions involving glucose has been found to increase (Sell et al 1996).  These modified molecules have been linked to several age related diseases.  There is a reduced accumulation of these damaged molecules on a regime of calori restriction (Masoro et al 1989).  This makes sense when you consider the fact that there is a decrease in glucose and insulin levels in calorie restricted animals.

All three of these ideas show possible ways in which calorie restriction might help to protect an organism from the degenerative effects of aging.  No one of them however can by itself offer a comprehensive explanation of the many system wide effects of placing an organism on a calorie restricted diet.

How Calorie Restriction works at the Molecular level

Calorie restriction has the below effects at the cellular level:

• An alteration in cellular defences
• A change in the expression of programmed cell death (apoptosis)
• Modification of energy production
• A change in the expression of the PNC1 gene
• An increase in the activity of the enzyme Sir2

Evidence is now pointing strongly to Sir2 and related enzymes (collectively known as Sirtuins) playing a major role in the modulation of cellular activity in a calorie restricted environment.  It has been shown that increasing artificially the levels of Sir2 in fruit flies does cause the flies to enter a state similar to that induced by calorie restriction.  Calorie restriction increases the life expectancy of a fruit fly by approximately 30%.  By artificially increasing the cellular levels of Sir2, an increase in life expectancy of 30% is also induced.

In yeast cells, two mechanisms have been identified that show how calorie restriction (together with other stressors such as heat) increases the levels of Sir2.  In the first pathway, calorie restriction turns on the PNC1 gene.  This gene produces an enzyme that removes the molecule nicotinamide (a molecule similar to B3) from the cells.  Nicotinamide represses Sir2 and thus removing it from the cells allows Sir2 activity to increase.

The second pathway that has been identified in calorie restricted yeast involves respiration itself.  Calorie restriction increases respiration, which  produces the enzyme NAD as a by-product, whilst lowering levels of the enzyme NADH.  Note that NAD activates Sir2, whilst NADH inhibits Sir2.  The result therefore is an overall increase in the activity of Sir2 in the yeast.

Anti-aging drugs.  Using medication to increase Sir2 expression

The key to utilising the knowledge gained through research into calorie restriction is to develop a drug that can mimic the effects of this diet.  A number of Sirtuin-activating compounds (or STAC’s) are currently being tested and results are so far positive.  One such STAC known as resveratrol is found in red wine and is also present in a number of species of plants when they are stressed.  When this compound is fed to yeast, worms or fruit flies their lifespan increases by 30%.  By exactly the same amount that would occur if they were placed on a calorie restriction diet.  One interesting point also is that the fruit flies on this regime do not suffer the loss of fertility that occurs in calorie restriction.

Where next?

Calorie restriction is one of the most exciting areas of aging research and if the current research is successful, could offer the possibility of increasing life expectancy in humans by 30%, simply by taking a pill.  It is early days still, but this area of research could one day affect all of our lives.

For more on Calorie restriction or to discuss this topic yourself join the Why we Age forum.

Mark S D'Arcy