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Cellular senescence was formally described more than four decades ago when Hayflick and colleagues showed that normal cells had a limited ability to proliferate in culture1 (see BOX1 for descriptions of different types of senescence). These classic experiments showed that human fibroblasts initially underwent robust cell division in culture. However, gradually over many cell doublings cell proliferation (used here interchangeably with cell growth) declined. Eventually, all cells in the culture lost the ability to divide. The nondividing cells remained viable for many weeks, but failed to grow despite the presence of ample space, nutrients and growth factors in the medium.
Soon after this discovery, the finding that normal cells do not indefinitely proliferate spawned two important hypotheses. At the time, both were highly speculative and seemingly contradictory. The first hypothesis stemmed from the fact that many cancer cells proliferate indefinitely in culture. Cellular senescence was proposed to be an anticancer or tumoursuppressive mechanism. In this context, the senescence response was considered beneficial because it protected organisms from cancer, a major lifethreatening disease. The second hypothesis stemmed from the fact that tissue regeneration and repair deteriorate with age. Cellular senescence was proposed to recapitulate the ageing, or loss of regenerative capacity, of cells invivo. In this context, cellular senescence was considered deleterious because it contributed to decrements in tissue renewal and function. For many years, these hypotheses were pursued more or less independently. However, as an understanding of the senescence response grew, these hypotheses coalesced, bringing new insights to the fields of cancer and ageing. Here, we review recent progress in understanding the causes
of cellular senescence, and the evidence that it is important for suppressing cancer and a possible contributor to ageing.
Senescence in an evolutionary context
To understand how cellular senescence can be both beneficial and detrimental, and the origins of its regulation, it is important to understand the nature of cancer and the evolutionary theory of ageing. Cancer is often fatal and therefore poses a major challenge to the longevity of organisms with renewabletissues. Tissue renewal is essential for the viability of complex organisms such as mammals. However, cell proliferation is essential for tumorigenesis, and renewable tissues are at risk of developing cancer2. Moreover, cancer initiates and, to a large extent, progresses...