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Published on: April 13, 2015
Telomeres at the nexus of aging, tumor suppression, and inflammation: toward an understanding beyond senescence
Samuel I Bloom1, Jan Karlseder2
1The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Abstract:
Aging is the greatest risk factor for most diseases. We propose that aging manifests as disease as a function of tumor-suppressive capabilities. Adequate tumor suppression results in cell death or an accumulation of damaged cells leading to inflammation and tissue dysfunction that underlies diseases such as cardiovascular disease, neurodegenerative diseases, or type 2 diabetes. Conversely, inadequate tumor suppression leads to cancer. Telomeres are central to this process because they oppose hyperproliferation that is required for cancer initiation by enforcing two potent tumor suppressor mechanisms: senescence and crisis. Although senescent cells promote age-related diseases via inflammatory signaling, crisis cells have lost the p53 and RB pathways, have more unstable genomes, and harbor shorter telomeres, all of which could increase inflammation to a greater degree than is seen in senescence. This model emphasizes the intimate relationship between aging, telomeres, tumor suppression, and inflammation and suggests that crisis cells may represent an unexplored driver of inflammation in advanced age.
Insights
Aging drives disease through tumor suppression. Crisis cells, with unstable genomes and shorter telomeres, may significantly increase inflammation in older adults, impacting age-related diseases.
Area of Science:
- Gerontology
- Oncology
- Cellular Biology
Background:
- Aging is the primary risk factor for numerous diseases, including cardiovascular disease, neurodegenerative diseases, and type 2 diabetes.
- Tumor-suppressive capabilities are proposed as a key factor in how aging manifests as disease.
- Telomeres play a crucial role in regulating cell proliferation and tumor suppression.
Purpose of the Study:
- To propose a model where aging manifests as disease based on tumor-suppressive capabilities.
- To investigate the role of telomeres, senescence, and crisis in aging and disease.
- To explore crisis cells as a potential driver of inflammation in advanced age.
Main Methods:
- Conceptual modeling based on existing literature on aging, cancer, and telomeres.
- Analysis of the mechanisms of senescence and crisis in relation to tumor suppression.
- Comparison of inflammatory signaling from senescent versus crisis cells.
Main Results:
- Adequate tumor suppression leads to cell death or damaged cell accumulation, causing inflammation and tissue dysfunction underlying age-related diseases.
- Inadequate tumor suppression results in cancer.
- Crisis cells, characterized by genomic instability and shorter telomeres, may induce greater inflammation than senescent cells.
Conclusions:
- Aging, telomeres, tumor suppression, and inflammation are intimately related.
- Crisis cells represent a potentially significant, yet unexplored, source of inflammation in aging.
- Understanding these mechanisms could offer new therapeutic targets for age-related diseases.
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