Aging - Get the Facts

by Dr. Lucy Nurek

Each of us has some personal experience with human aging and the overriding impression is that aging is the result of some fundamental and unchangeable property of life. Philosophers and scientists have been interested in the aging process for a long time. For centuries people have believed that aging is natural, that it is not a disease and it cannot be treated.

It has always been assumed that aging is an unavoidable process
that could not and should not be interfered. Within the past decades however, on the basis of new clinical studies, scientists and physicians are beginning to open up their minds and see the
aging from a different perspective. Aging is now considered a multi-factorial process with many abnormal events occurring.

Aging and senescence defined
The term aging is used in various ways. It means all changes that occur in the body with the passage of time - including the  rowth, development and increasing functional efficiency that occur from birth to adulthood, as well as the degenerative changes that occur later in life. Senescence refers to the combination of  processes of deterioration which follow the period of development of an organism. The term aging has become so commonly equated with senescence that the terms are often used  nterchangeably.

Theories of aging
Although we know that our genes influence aging and
longevity, how exactly this takes place on cellular and chemical
levels is just partially understood. Several aging theories have been proposed in an attempt to explain this phenomenon. Many
of them are interlinked, in the same complex way the biological
processes of the body are interlinked.  While none of these theories conclusively define the physiological mechanisms of aging, many do seem credible. They can largely be categorized into two groups of theories. Some researchers uphold that aging is an intrinsic (inborn) process governed by inevitable or even
preprogrammed changes in cellular function. Others attribute
aging to extrinsic (environmental) factors that progressively
damage our cells over the course of a lifetime. The following  outlines some of these theories briefly.

The free radical theory
One of the most popular theories of aging is the free radical theory. This theory was first proposed by Dr. Denham Harman in
1954, and postulates that aging results from an accumulation of
changes caused by reactions in the body initiated by highly  reactive molecules known as "free radicals".1,2 A free radical is a
molecule carrying an unpaired electron. All free radicals are exceptionally reactive and will hunt for and obtain an electron in
any way possible. Free radicals will attach themselves to other
molecules, and steal electrons from them (process called  oxidation). They convert these molecules into new free radicals or alter their chemical structure. A certain percentage of these reactive radicals combine with and oxidize important cellular structures, thus impair their activity. The DNA and RNA molecules
that carry on genetic material may also be damaged, which can
lead to mutations and cell death.

The changes induced by free radicals are believed to be a major cause of aging, development of diseases, or death.3-7 The free radicals may be produced endogenously (within the body)  through normal metabolic processes, or exogenously (outside the body) from sources such as pollution, radiation or cigarette smoking.

It has been estimated that during normal metabolism, each cell produces more than 20 billion molecules of free radicals per day.
This number rises when cell metabolism is disrupted!

The mitochondrial theory
The mitochondrial theory is interlinked with free radical theory.
8,9 There is such a strong connection between these two theories that they are often discussed together.

Mitochondria produce about 90% of free radicals and are themselves the primary sites for free radical damage. Since mitochondrial DNA has no histone (proteins) protection or significant enzymatic repair systems as nuclear DNA has, consequently, mitochondrial DNA is far more subject to free radical damage than nuclear DNA.10,11 Extensive damage accumulates over time and shuts down mitochondria,
causing the cells to die.12-15 This leads to changes in the structures of tissues and alters their functions, which manifest as aging and chronic degenerative diseases like arthritis, atherosclerosis, neurodegenerative diseases, and cancer.7,13

In the past decade, more than one hundred mitochondrial DNA
mutations have been found in patients with mitochondrial disease, and some of them also occur in aging human tissues.10
The incidence and abundance of these mutant mitochondrial DNAs are increased with age, particularly in tissues with great demand for energy.10 Evidence indicates that one mechanism for nerve and muscle dysfunction with age involves the  mitochondria.16-18 Recent studies have also revealed that the ability of the human cell to cope with oxidative stress
declines with age.10,19

The programmed cell death theory
Some scientists believe that atrophy of the organs is an effect of programmed cell death Mitochondria, called "powerhouses of a cell", are membrane-enclosed tiny regions of the cell that manufacture chemical energy (ATP molecules) that is needed to carry on cellular processes. Mitochondria are present in virtually
all human cells except red blood cells. There may be from few to several thousand mitochondria per cell, depending on cell activity. One of the unique features of mitochondria is that they contain their own mitochondrial DNA (genetic material). Mitochondria can also reproduce themselves. Although mitochondria appear to be semi-autonomous, separate units within our cells, in fact they are completely dependent functionally on many proteins and enzymes that are made by other parts of the cell and are programmed

by nuclear DNA. (apoptosis). After a certain number of cell divisions or at the certain age, cells may activate a "suicide
program" that destroys their own DNA. Recent evidence indicates
that mitochondria exhibit major functional and structural
changes that serve to regulate apoptosis.20-26 Various apoptotic signals, such as radicals, lead to mitochondrial release of proapoptotic proteins.20-22

Apoptosis is a process that goes on continuously throughout
our life. It is involved in embryogenesis (the formation and growth of an embryo) for proper organ and tissue development.
After birth and through adulthood, it helps eliminate unneeded
and damaged cells. However, there is evidence that advanced
age is associated with dysregulation of apoptosis.27 Several studies have shown age-related changes in the levels of proteins
and factors that regulate apoptosis. 20-23 This could explain the ageassociated increased prevalence of cancers, certain autoimmune diseases, and neurodegenerative disorders in older people.27 Also, a variety of evidence has supported an apoptotic contribution to neuronal loss in Parkinson's disease28 and Alzheimer's disease.29

Supporting research

1. Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol 1956;11: 298-300
2. Harman D. Free radical theory of aging: history. EXS. 1992;62:1-10

3. Harman D. Free radical theory of aging. Mutat Res 1992 Sep;275(3-6):257-66

4. Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci. 2006 May;1067:10-21

5. Beckman K. & Ames B. The free radical theory of aging matures. Physiol Rev 1998;78: 548-81
6. Mezzetti A. et al. Systematic oxidative stress and its relationship with age and illness. J Am Geriatr Soc 1996 Jul;44(7):823-7

7. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002 Jan;82(1):47-95

8. Harman D. The biological clock: the mitochondria? J Am Geriatr Soc 1972;20: 145-47.

9. Miquel J. et al. Mitochondrial role in cell aging. Exp Gerontal 1980;15: 579-91.

10. Wei YH et al. Mitochondrial theory of aging matures-roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei). 2001 May;64(5):259-70

11. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol. 1995 Jul;27(7):647-53

12. Kim R et al. Regulation and interplay of apoptotic and non-apoptotic cell death. J Pathol. 2006 Feb;208(3):319-26

13. Fiskum G et al. Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease. Ann N Y Acad Sci. 2003 Jun;991:1ma11-19

14. Peng TI et al. Visualizing common deletion of mitochondrial DNA-augmented mitochondrial reactive oxygen species generation and apoptosis upon oxidative stress. Biochim Biophys Acta. 2006 Feb;1762(2):241-55

15. Liu CY et al. Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. Ann N Y Acad Sci. 2004 Apr;1011:133-45

16. Cottrell DA et al. Mitochondrial DNA mutations
in disease and ageing. Novartis Found Symp. 2001;235:234-43

17. Brierley EJ et al. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann Neurol. 1998 Feb;43(2):217-23

18. Pesce V et al. Age-related mitochondrial genotypic and phenotypic alterations in human skeletal muscle. Free Radic Biol Med. 2001 Jun 1;30(11):1223-33

19.Wei YH & Lee HC.Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002 Oct;227(9):671-82.

20. Pollack M et al. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y Acad Sci. 2002 Apr;959:93-107

21. Pollack M & Leeuwenburgh C. Apoptosis and aging: role of the mitochondria. J Gerontol A Biol Sci Med Sci. 2001 Nov;56(11):

22. Phaneuf S & Leeuwenburgh C. Cytochrome c release from mitochondria in the aging heart: a possible mechanism for apoptosis with age. Am J Physiol Regul Integr Comp Physiol. 2002 Feb;282(2):R423-30

23. Leeuwenburgh C. Role of apoptosis in sarcopenia. J Gerontol A Biol Sci Med Sci. 2003 Nov;58(11):999-1001

24. Hetz Ket al. Beyond apoptosis: nonapoptotic cell death in physiology and disease. Biochem Cell Biol. 2005 Oct;83(5):579-88

25. Green DR & Reed JC. Mitochondria and apoptosis. Science. 1998; 281:1309-1312

26. Susin SA et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J.Exp. Med. 1999;189:381-394.

27. Joaquin AM. & Gollapudi S. Functional Decline in Aging and Disease: A Role for Apoptosis. Journal of the American Geriatrics
Society 2001;49 (9), 1234-1240

28. Tatton WG et al. Apoptosis in Parkinson's disease: Signals for neuronal degradation. Annals Neurology 2003 Mar;53(S3): S61-S72

29. Mattson MP et al. Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res. 1998 Oct 5;807(1-2):167-76