The first four hallmarks -genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis, have been classified as primary hallmarks because they are the primary causes of cellular damage (Figure ). They are all, unequivocally, negative. The next three hallmarks -dysregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence -are classified as antagonistic because they are related to the responses to the primary hallmarks. Contrary to the primary hallmarks, antagonistic ones have multidimensional effects -initially these responses mitigate the damage caused by the primary hallmarks, but eventually become harmful themselves. For example, cellular senescence, or cell cycle arrest, can protect the organism from cancer, but also promote aging. The last two hallmarks -stem cell exhaustion and altered intercellular communication -have been characterized as integrative since they take place when the accumulated damage, resulting from the primary and antagonistic hallmarks cannot be compensated by the cellular homeostatic mechanisms and reparative processes. Integrative hallmarks further promote deterioration of cells that are responsible in due course for aging. Both of these hallmarks influence tissue homeostasis and function.