It is well-known that aging is the most risk factor for Alzheimers disease (AD). Recent studies have demonstrated that human telomerase is associated with pathological mechanisms of AD. In view of the central role of telomere and telomerase in the aging process, herein we found that the aggregated form A beta (A beta 1-40 and A beta 1-42), not A beta monomer, could inhibit telomerase activity both in vitro and in living cells. The beta-sheet structures were essential for A beta-induced telomerase inhibition. Further studies indicated A beta oligomers inhibited telomerase activity through binding to DNA center dot RNA hybrid formed by telomeric DNA and the RNA template of telomerase, then blocking telomerase elongation of telomeric DNA. We also identified that intracellular A beta localized at telomere, and induced cell senescence and telomere shortening. These results indicate that A beta oligomers can be potential natural inhibitors of telomerase and that inhibition of telomerase activity may be one of the factors for A beta-induced cytotoxicity. Our work may offer a new clue to a better understanding of aging and AD.