**5. Conclusions**

The regenerative capacity of many stem cells declines functionally with age and, this decline triggers in part many age-related symptoms, and the development of certain diseases. Recent evidences have demonstrated that certain tumor suppressors, like *p16INK4a*, also suppresses the proliferation of stem or progenitor cells in the bone marrow, pancreas and brain. Thus, p16INK4a seems to balance equilibrium reducing cancer incidence, which promotes longevity, but also decreasing stem cell self-renewal and proliferation, compromising tissue regeneration and repair, which are likely to reduce longevity. These observations allow us to suggest the provocative but unproved hypothesis that mammalian aging results in part from the beneficial efforts of tumor suppressor proteins to interdict cancer. In this stage, characterization of how stem cells age, such as **the characterization of reliable biomarkers,** deregulated signaling pathways, loss of self-renewal or acquisition of defects in differentiation of stem cells, will contribute to understand the age-associated pathophysiological decline. Likewise, it is also essential to figure out the cellular and molecular components of stem cell niches, how the niche changes during aging, and

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#### **6. Acknowledgement**

This work was supported by the Human Frontiers Science Program Organization, the Spanish Ministries of Science and Innovation (SAF2010-15386) and Health (FIS PI06/0627). We thank Simon Bartlett for editing assistance. The CNIC is supported by the Ministry of Science and Innovation and the Pro-CNIC Foundation.
