Proteases are a set of enzymes that have been involved in multiple biological processes throughout evolution. Among them, extracellular matrix (ECM) remodeling has emerged as one of the most relevant functions exerted by these proteins, being essential in the regulation of critical events such as embryonic development or tissue homeostasis. Hence, it is not surprising that dysregulation in any protease function that affects ECM homeostasis may contribute to the aging process. Matrix metalloproteinases (MMPs) are one of the most important families of proteases involved in the tight control of ECM remodeling over time. In this review, we will discuss how MMPs and other proteases alter ECM composition and mechanical properties in aging, thereby affecting stem cell niches and the development of senescent phenotypes. Finally, we will summarize recent findings that associate MMPs with the development of age-related diseases, such as neurodegenerative disorders.