Telomerase induction in T cells: A cure for aging and disease?

Abstract

Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 co-stimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8 + CD28 − T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically-suitable formulation.

Editorial

“…If in depression, shortened telomeres and heightened risk for medical illness bear causal relationships with each other, then telomere shortening could provide a 'missing link' to explain the higher-than-expected medical morbidity seen in depression (Musselman 1998;Brown 2004). Also, to the extent that telomere pathology is important in the pathophysiology of various illnesses, discovering the biochemical mediators leading to telomere shortening could lead to new classes of medications (Effros 2007). It is still not known if depression leads to accelerated 'aging' of mitotic cells.…”

“…If PBMC telomere dynamics directly mirror CNS ones (especially in mitotic cells such as hippocampal stem cells), this could help us understand cell-level pathology in the brain in depressed patients. Even if PBMC telomere length bears no relationship to hippocampal cell telomere length, shortened PBMC telomeres could still be significant in depression: (1) if shortened telomeres in peripheral immune cells eventuate in premature aging of those cells, this could result in impaired immune responsiveness and in hypersecretion of pro-inflammatory cytokines (Effros 2007;Leonard 2000); (2) as noted above, shortened telomeres have been associated with a variety of human medical illnesses, such as cardiovascular disease (Cawthon et al 2003) and dementia (von Zglinicki et al 2000;Franco et al 2006;Honig et al 2006;Martin-Ruiz et al 2006). If in depression, shortened telomeres and heightened risk for medical illness bear causal relationships with each other, then telomere shortening could provide a 'missing link' to explain the higher-than-expected medical morbidity seen in depression (Musselman 1998;Brown 2004).…”

The Szilard Hypothesis on the Nature of Aging Revisited

“…When telomere lengths are measured in somatic cell cultures, a correlation is observed between telomere length and the number of cell divisions preceding senescence and death (Allsopp et al 1992). However, there is now a consensus that telomere length correlates to but does not cause aging in most individuals, with immunosenescence being the most tangible correlate (Effros 2007). Exceptions may be a variety of rare premature aging syndromes, such as dyskeratosis congenita (Kirwan and Dokal 2008) and idiopathic pulmonary fibrosis (Blasco 2005), and some cases of liver cirrhosis (Wiemann et al 2002) and myelodysplastic syndromes (Ohyashiki et al 1994), where mutations in telomere maintenance genes have been identified.…”

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

“…The immunological history of humans cannot, therefore, be mimicked in laboratory animals, which are subject to minimal exposure to such antigens [126]. Due to the extraordinarily low frequency of T cells specific for any single antigen, immune responses require a massive degree of proliferation in order to adequately control infection.…”

“…Telomerase activation should prevent this telomere shortening and allow the body's immune system to fight a chronic infection indefinitely. Telomerase activation is a potential treatment for AIDS [126]. Although improved immunity cannot be considered a "cure" for aging and disease, the beneficial effects promise to enhance health and quality of life of the elderly and of persons infected with HIV-1, a disease characterized by accelerated aging of the immune system.…”