1. DNA Damage, Aging, and Cancer From Age-related and Telomere Concept

2. Aging and Cancer: Aging is a syndrome of changes that are deleterious, progressive, universal and thus far irreversible. Some scientist prefer to use the word senescence because "aging" implies that the passage of time necessarily results in deterioration! Nada ALmutairi There is a distinction between aging and cancer is suggested by the fact that ionizing radiation increases cancer rate, but has less effect on the rate of aging [RADIATION RESEARCH; Preston,DL; 160(4):381-407 (2003).

3. when DNA repair is defective cells can respond by inducing cellular senescence or apoptosis; preventing cancer, but accelerating aging. With aging the declining efficiency of cellular mechanisms means that cancerous cells will be eliminated by apoptosis. Nada ALmutairi but defective DNA repair leads to aging. DNA damage due to mutagens leads to cancer Cancer is a disease of DNA; Non-dividing cells like neurons or muscle cells don't become cancerous, but aging affects all tissues aging is a disease of all organs;

4.  Experimental animals subjected to chronic sublethal ionizing radiation (alpha−, beta−, gamma− & X−rays that cause atoms & molecules to form ions) have shown generalize atrophy ("premature aging") and shortened lifespans, but single X−ray & ionizing radiation exposures have more noticeably increased kidney degeneration and cancer (especially leukemia). Other mutagens increase the risk of tumor-formation without reducing maximum lifespan.  Spontaneous mutations & chromosome breakage are not normal contributors to aging! Nada ALmutairi

6. It can be age-related decline in cell proliferation rate  the time between two cellular doublings increases with the age of an organism for cells appertained to the same stage of their replicative life.  For example, stem cells taken from old mice proliferate slower than the stem cells taken from young mice (de Haan etal. 1999). Or, an increase in proportion of replicatively senescent cells in an organism with age  that cells decline in proliferative potential with each cell doubling.  This means that they decrease in the number of divisions left before entering.  the state of irreversible growth arrest Called “replicative aging”. Nada ALmutairi

8. Cancer Risk increasing with aging(based on cancer mortality) Cancer rate declination with aging (based on incidence data) Nada ALmutairi Cancer incidence rate (1988-92), average annual, and mortality rate (1990) in the USA (IARC 1997, Health US 1996-1997, Smith 1996).

9.  Most researchers who studied relationships between age and cancer risk paid attention mainly to the increase in cancer risk with age (Peto et al. 1975, Rainsford et al. 1985, Volpe and Dix 1986, Dix 1989, Krtolica and Campisi 2002).  They ignored other typical features of the cancer rate pattern such as the deceleration and the decline in the rate at old ages.  One reason for this might be the use of data on age-specific cancer mortality rather than incidence data. Nada ALmutairi Cancer Risk increasing with aging(based on cancer mortality) Cancer rate declination with aging (based on incidence data)

10.  Conclude that, Risk of dying from cancer among oldest old decline with age. Nada ALmutairi

11.  Telomeres consist of the six-base repeating sequence TTAGGG. With each cell division, some of the telomere is lost because DNA polymerase cannot complete the 5'−end and therefore leaves a single-strand 3'−end overhang.  For humans, the length of the remaining telomere is usually an indicator of how many divisions a dividing cell has left.  Once the telomere is gone, functional genetic DNA would be lost with each cell division. Prior to complete erosion of the telomere a signal is sent to p53 protein to stop the cell cycle causing the cell to go into a slow-decaying, non-replicative state known as replicative senescence. Nada ALmutairi

12. Telomeric Repeat-binding Factors (TRFs). TRF1 regulates telomere length, assisting the telomerase enzyme. TRF2 models the telomere into the T−loop structure. TRF2 may be protecting the single-stranded 3'−end overhang from degradation, and prevents DNA damage response. Loss of TRF2 from telomeres directly signals apoptosis. Telomerase is a reverse transcriptase, meaning an enzyme that makes DNA from an RNA template. In human germ cells or 85% of cancer cells human TElomerase Reverse Transcriptase (hTERT) and an RNA template are sufficient conditions for the creation of new telomeres. Nada ALmutairi

13.  These patients have lost telomerase function, resulting in a defect of the preservation of telomere length. Analysis of cells from dyskeratosis congenita patients reveals telomere shortening and dysfunction compared with that in the cells of age-matched controls.  Patients suffering from this disease manifest several distinct abnormalities, including abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, bone-marrow failure and cancer disposition. Telomere Dysfunction Linking Aging and Cancer Nada ALmutairi

14. So,  Telomere shortening apparently has a dual role in tumor development and progression. On the one hand, it induces chromosomal instability and the initiation of cancer; on the other hand, tumor progression requires stabilization of telomeres  Thus, telomere shortening results in phenotypes of aging and also causes genomic instability.  The cellular response to telomere dysfunction senescence and apoptosis might contribute to aging phenotypes. However, it is only in cells that have lost the checkpoint functions (tumor suppressor functions) that involve apoptosis and senescence that telomere dysfunction can lead to the genomic instability that fuels cancer. Nada ALmutairi

15. So,  Defects in proteins required to maintain telomere function can also lead to chromosome instability and cancer [EXPERIMENTAL GERONTOLOGY 36:1619-1637 (2001)]. Telomerase expression can actually make cells more resistant to apoptosis induced by oxidative stress [FEBS LETTERS; Ren,J; 488:133-138 (2001)].  If cells continue to divide after having lost their telomeres (ie, beyond the Hayflick Limit of about 50 cell divisions), they not only become malfunctional due to lost genes, but the chromosome ends start sticking to other chromosomes increasing the number of abnormalities. Typically a cell will invoke apoptosis ("cell suicide") or become senescent (stop the cell cycle) to prevent the cell from dividing or becoming cancerous. The Hayflick Limit itself may be a means of preventing cancer. Nada ALmutairi

16. Summary,  Stop cell division is not the only way to cure cancer or stop aging, telomeres aspect is must consider.  From the length of telomere, they can detect the times cell got in division; from this theory it could be measure the length of telomere and could be indicator for cancer cell, by making some target that define specific length of telomere and inhibits it's telomerase activity!  Or shortening the RNA that will synthesize the telomere from. Nada ALmutairi

17. At the end,  Maintained genome is first treatment for cancer and aging, thus damage DNA from defect in single gene to chromosomal instability with the negative effect of aging could cause cancerous cells.  But must consider other mechanism in maintaining genome; includes a complex telomere processing machinery and the integrity of mitochondrial DNA.  Beside the multiple repair pathways, each focusing on a specific category of DNA lesion, and various checkpoint. Nada ALmutairi