AGING

See also autoimmunity See also atherosclerosis See also Alzheimers

Abnormalities associated with Aging

The gadual deterioration in immune fuction that occurs with aging has been termed immune senescence This is manifest both as reduced in vitro immune responsiveness and impaired immune response to vacination and acute infection.

Telomere Shortening has been reported to be associated with aging. Telomeres are located at the ends of chromosomes. Telomeres maintain chromosomal integrity and length.

    Telomeres are synthesized by the enzyme telomerase which is lacking in normal somatic cells. Cell senescence resulting from shortened telomeres in somatic cells forms the basis for the telomere theory of aging. In telomerase-negative differentiated somatic cells, cell senescence can actually be delayed and reversed by transfecting the cells with vectors encoding the human telomerase reverse transcriptase (hTERT) which is the active catyltic component of telomerase.

    Interestingly, while aging is associated with loss of telomerase activity and telomere shortening in most somatic cells, most cancer cells demonstrate increased telomerase actvity with varying lenghts of telomeres. Yet increasing age is the strongest risk factor for most cancers.

    hTERT appears to be regulated by different transcription factors in various cellular contexts. For example, two important c-Myc binding sites (CACGTG, referred toa s E boxes) are present in the hTERT core promoter and c-Myc is considered an important activator of telomerase. E6 human papilloma virus type 16 protein and other factors appear to be able to cooperate with c-Myc to activate transcription of hTERT.

CD8+ T cells which lack CD28: A major feature of immune senescence is the accumulation of clonally expanded memory CD8 T cells characterized by the lack of CD28 expression. The proportion of CD8+ T cells that lack surface expression of CD28 increases with age so that in adulthood, 25-50% of CD8+ T cells are CD28-. In acute viral infections, there is often considerable rapid expansion of CD8+CD28- antiviral effector T cells. Upon antigenic stimulation, these CD8+CD28- T cells produce interferon gamma, but not IL-2 and proliferate poorly.

The phenotype CD57+CD28- T cell subset observed in old age donors may reflect increases in CMV specific CD 8 T cell fequencies. This phenotype has also been reported in other setting such as rheumatoid arthritis and HIV-1 infection.

Abnormalities in CMV positive Elderly:

    Polarization towards Effector Memory Cells in CMV elderly: CMV  specific CTL have a highly polarized membrane phentoype that is typical of effector memory cells (CD28-, CD57+, CDR7-)

    Restricted TCR in CMV sepcific CTL: TCR has shown that CMV specific CTL have highly restricted clonality with greater restriction in the larger expansions. 33% more clonal expansion were observed in CMV seropositive donors compared with negative individuals. These data implicate CMV  a major factor in driving oligoclonal expansions in old age. Such an accumulation might impair the ability to respond to heterologous infection and may underlie the negative influcucne of CMV eropositivity on survival in the very elderly.

    bcl-2+ CMV specific T cells: It was reproted that CMV specific T cells are uniformly bcl-2+, indicating resistance to apoptosis, which is reminiscent of cells that have reached replicative senescence in cell culture.