BASICS OF AGING THEORIES AND DISEASE RELATED AGING - AN OVERVIEW

 

DISEASES INDUCED AGING
Aging is the major risk factor for the predominant killer disease of developed countries, including dementia, cardiovascular disease and cancer etc.

a. Telomere and age related disease
It is well established that telomere length and telomerase activity are important factors in the pathogenesis of human diseases[10]. Telomerase activation may prove to be useful in the treatment of chronic and degenerative diseases associated with telomere loss We summarize information on the age-related diseases below, which have been proposed to be related to telomeres.

i. Cardiovascular diseases
Atherosclerosis is also an aging-related systemic disease. Telomere length is a new marker of cardiovascular risk. In the vascular endothelium, shorter telomeres are found in those areas of the arterial wall that are more susceptible to atherosclerosis because of higher haemodynamic stress. It is believed that this stress results in a more rapid cell turnover In addition, vascular endothelial cells and smooth muscle cells in the vicinity of atherosclerotic lesions often stain positive for the activity of β-galactosidase, which is a rather nonspecific marker for cellular senescence[11]. Furthermore, the induction of telomere dysfunction in endothelial cells in vitro generates a senescent phenotype with an atherogenic protein expression profile. Healthy individuals with shorter telomere were likely to develop hypertension, and hypertensive individuals with shorter telomere were more susceptible to develop atherosclerosis. Heart failure is a frequent cause of death in the aging human population. Telomere shortening with age might also contribute to cardiac failure in humans, opening the possibility for new therapies. Chronic heart failure is characterized by increased myocyte apoptosis and telomere erosion. In humans, the formation of myocytes from telomerase-positive cardiac stem cells appears to be necessary for cardiac homeostasis.

ii. Diabetes
Type 2 diabetes is caused by a combination of peripheral insulin resistance and b-cell dysfunction. Telomeres were significantly associated with type 2 diabetes, which could be partially attributed to the high oxidative stress in the patients with type 2 diabetes. Moreover, short telomeres are predictors of progression of diabetic nephropathy and of all-cause mortality in the patients with type 1 diabetes.

iii. Cancer
The classical telomere hypothesis suggests that the telomere shortening provides a tumor suppressor mechanism to cease the growth of transformed cells. In normal somatic cells, the absence of telomerase can lead to telomere shortening and cell senescence. However, the majority of cancer cells exhibit a high telomerase activity. The reappearance of telomerase activity is triggered by as yet unclear molecular mechanisms and enables cancer cells to maintain telomere length. Studies have revealed a dual role of telomere shortening in carcinogenesis. On the one hand, shortened telomeres induce chromosomal instability, which is the most important cause of cancer initiation during aging. On the other hand, telomere stabilization is required for tumor progression. The initiation of chromosomal aberrations by telomere shortening might contribute to the increased cancer rate of cancer onset during aging. Additionally, telomere shortening may initiate the tumor genesis of gastric carcinoma. The ongoing basic research in this field helps to constantly define new targets and to increase the specificity, safety and efficacy of existing therapeutic approaches directed against telomeres and telomerase. Therefore, therapies targeting telomerase with telomerase inhibitors revealed the potential for cancer therapy. Recent research developments for each of the anti-telomerase approaches including antisense-oligonucleotides, hammerhead ribozymes, dominant negative hTERT, reverse-transcriptase inhibitors, immunotherapy, G-quadruplex stabilisers, gene therapy, small molecule inhibitors and RNA interference have been provided[12].

iv. Immune system diseases
The immune system is a prime example of a highly dynamic cellular system, for which telomere maintenance is pivotal. Immune competence is strictly dependent on rapid expansions of clonal T- and B-cell populations, and telomere loss may contribute to defective immune responses in the elderly. Equally interestingly, accelerated T-cell aging combined with telomeric shortening may prompt an autoimmune response and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly. Recent reports have suggested that telomere shortening is involved in the dramatic age-related alterations of the immune system, and this is considered one of the major factors affecting morbidity and mortality. The gradual decline with age in the capacity of the immune system to recognize and eliminate antigens is an important causal factor for many diseases in the elderly. Although both the innate and adaptive immune responses are weakened in old people, it is the decline in T-cell action that proves to have the most injurious effect on the elderly. T cells become clonally exhausted which leads to a decline in the adaptability of the response of the immune system[13]. The senescence of T cells in vivo is well documented: as the number of population doublings in culture increases then there is a progressive decrease in the proportion of T cells that express CD28. This results in an inability of the T cells to proliferate and a reduction in telomerase induction by CD28, as well as a resistance to apoptosis. In addition, research on bone marrow transplantation has provided important clues for the in vivo interactions of immunosenescence and telomere length and consequences.

v. Dyskeratosis congenital
Defective telomere function or mutations in the DNA repair system can induce some human disorders associated with shorter telomere length, such as dyskeratosis congenital (DC)[14]. Most direct evidence for telomere shortening during human aging comes from research on DC, which is a premature aging disease characterized by telomerase and telomere dysfunction. Autosomal dominant dyskeratosis congenital is associated with mutations in the RNA component of telomerase, while X-linked dyskeratosis congenital is due to mutations in the gene encoding dyskerin.

b. Alzheimer’s disease
Brain damage and the death of brain cells affect brain function and cognitive ability.  The prevailing paradigm of Alzheimer’s disease pathogenesis contends that the primary pathogenic event is the extraneuronal or intraneuronal, or both, accumulation of the misfolded protein, amyloid beta-peptide which initiates a pathogenic cascade resulting in neurotoxicity and ultimately the clinical syndrome of Alzheimer’s disease. This paradigm has its origins in the autosomal  dominant forms of the disease, which account for 1–2% of all cases. These inherited forms are associated with mis-sense mutations of genes that encode the amyloid precursor protein (APP), or proteolytic enzymes that cleave APP (eg, presenilin 1 and 2). Such mutations are associated with an increased production of amyloid beta peptide and result in early-onset of aging.

c. Parkinson’s Disease
Parkinson’s disease is a progressive neurodegenerative disease, the second most common disorder of this type after Alzheimer’s disease. It progresses slowly as small clusters of dopaminergic neurons in the midbrain die. The gradual loss of these neurons results in reduction of a critical neurotransmitter called dopamine, a chemical responsible for transmitting messages to parts of the brain that coordinate muscle movement. Common motor symptoms are tremors or shaking in hands, arms, legs, jaw, and face; rigidity or stiffness of limbs and trunk; bradykinesia, or slowness of movement; and difficulties with balance, speech, and coordination. Symptoms begin gradually and typically worsen over time. There is also a collection of nonmotor symptoms, such as poor sense of smell, constipation, depression, cognitive impairment, fatigue, and other impairments that also accompany Parkinson’s. Some of these symptoms may develop years before the onset of motor problems.

Figure 3: Parkinson’s patients have less dopamine

d. Premature Aging
Premature aging, called also accelerated aging, is a group of genetic syndromes, in which the children have premature aging. The three known premature aging syndromes of human being are Hutchinson–Gilford Progeria Syndrome (HGPS), Werner syndrome (WS), and Cockayne syndrome (CS). These syndromes have differences on genetic backgrounds, on ages of onset of abnormity, and on symptoms; however they are common on typical aging changes, including hair loss, tooth loss, thinness and hardness of skin, skin wrinkles, and senior spots. The abnormality in tissue structure is the common point between premature aging and normal aging, and it links a defective development and a defective repair, the Misrepair. Defective development is a result of mis-construction of tissues/organs, as a consequence of genetic mutation; whereas aging is a result of mis-reconstructions, the Misrepairs, for maintaining the structure of tissues/organs. Construction-reconstruction of the structure of an organism is thus the coupling point between development and aging. Mis-construction and Mis-reconstruction (Misrepair) are the essential processes in the development of aging-like feathers. Misrepair is defined as incorrect reconstruction of an injured living structure such as a molecule, a cell and a tissue.

Hutchinson–Gilford Progeria Syndrome (HGPS) is the first syndrome that is named as premature aging syndrome or Progeria. HGPS is a genetic condition with abnormal development and appearance of premature aging features from infancy[15]. The Progeria children often look normal at birth; however they manifest the abnormal growth after  birth. Growth abnormalities develop progressively with age, including growth failure, hair loss, hardening and thinness of skin, wrinkled skin, stiff joints, atherosclerosis, and loss of body fat and muscle. HGPS children all have a small body but big head with prominent eyes and narrow face, and they die mainly from heart attack or stroke in young ages. A gene mutation on lamin A (LMNA gene), a protein for composing nuclear lamin, is identified in the HGPS patients. Werner syndrome (WS), called also “adult progeria”, is a genetic disorder characterized by an early and progressive development of aging features[15]. A mutation on WRN gene was identified in the WS patients. Normal WRN protein is a kind of DNA helicase, and it assists DNA duplication and maintains the functionality of telomeres.

Cockayne syndrome (CS), called also “Weber-Cockayne syndrome” and “Neill-Dingwall syndrome”, is a rare genetic condition characterized by growth failure, impaired development of neural system, abnormal sensitivity to sunlight, and appearance of premature aging.

CONCLUSION
Aging is a syndrome of changes that are deleterious, progressive universal and thus for irreversible. Several theories have been applied in support of aging. It is a cellular process, or a genetic process that every individual has to be gene through. It cannot be stopped at all but can be reduced the rate by various therapies. Recently various approaches are emerged towards the preventer of aging. In recent years various advancements in this field has be noted. Branded products have a good success rate that referral product. Though now days, polyherbal technology has offered a new light in anti-aging treatment. Moreover disease induced aging are more prevalent with lot of disorders. So disease specific drugs are formulated to have few roles as anti-aging therapy. Novel approaches such as Rapalogs and sirtuin1 analogs have brought a promising contribution as noted for preclinical data. Clinical studies are now being conducted at several centers to figure at potential role of new molecules with less toxic effects. So, it can be concluded that our review clearly explain the theory and etiology behind aging and their possible treatments either clinically or by some others means.

REFERENCES
1. Martin G.M., Austad S.N. and Johnson T.E; Genetic analysis of ageing: Role of oxidative damage and environmental stress; Nat. Genet; 1996; 13; 25-34.
2. Davies K.J; Oxidative stress: the paradox of aerobic life; Biochem. Soc. Symp; 1995; 61; 1-31.
3. Martin G.M; Interaction of aging and environmental agents: The gerontological perspective; Prog. Clin. Bio. Res; 1987; 228; 25-80.
4. Gilca M., Stoian I., Atanasiu V. and Virgolici B; The oxidative hypothesis of senescence; J. Postgrad. Med; 2007; 53; 207-213.
5. Harman D; Aging: a theory based on free radical and radiation chemistry; J. Gerontol; 1956; 11; 298-300.
6. Sohal R; Role of oxidative stress and protein oxidation in the aging process; Free. Radic. Biol. Med; 2002; 33; 37-44.
7. Schulz T.J., Zarse K., Voigt A., Urban N., Birringer M. and Ristow M; Glucose Restriction Extends Caenorhabditis elegans Lifespan by Inducing Mitochondrial Respiration and Increasing Oxidative Stress; Cell. Metab; 2007; 6; 280-293.
8. Hagen T.M; Oxidative stress, redox imbalance, and the aging process; Antioxid. Redox. Signal; 2003; 5; 503-506.
9. Yang J.H., Lee H.C., Lin K.J. and Wei Y.H; A specific 4977- bp deletion of mitochondrial DNA in human aging skin; Arch. Dermatol. Res; 1994; 286; 386-390
10. Shammas M.A; Telomeres, lifestyle, cancer, and aging; Cur. Opinion. Clin. Nutr. Metab. Care; 2011; 14; 28–34.
11. Yang Z.W., Huang X., Jiang H., Zhang Y.R., Liu H.X., Qin C. and Eisner G.M; Short telomeres and prognosis of hypertension in a chinese population; Hypertension; 2009;  53; 639–695.
12. Agrawal A., Dang S. and Gabrani R; Recent patents on anti telomerase cancer therapy; Recent. Pat. Anticancer. Drug. Discov; 2012; 7; 102–117.
13. Akbar A.N., Beverley P.L. and Salmon M; Opinion: will telomere erosion lead to a loss of T-cell memory?; Nat. Rev. Immunol; 2004; 4; 737–743.
14. Mitchell J.R., Wood E. and Collins K; A telomerase component is defective in the human disease dyskeratosis congenital; Nature; 1999; 402; 551–555.
15. Katayama K., Armendariz-Borunda J., Raghow R., Kang A.H. and Seyer J.M; A pentapeptude from type I collagen promotes extracellular matrice production; J Biol.Chem; 1993; 268; 9941-9944.

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