Correlations Between Mechanisms of Aging and Diseases of Aging
Researchers here mine a very large data set to establish whether age-related diseases linked to a specific underlying single causative mechanism of aging will show up together in patients more often than not. One would expect that they will. To pick one example, multiple age-related diseases appear likely to be primarily caused by the increased presence of senescent cells in old tissues. A patient's senescent cell burden will thus largely determine the risk of suffering from all of those conditions. Patients exhibiting one condition, most likely because they have more senescent cells than their healthier peers, should be more likely to also exhibit other conditions in that set.
Age-associated accumulation of molecular and cellular damage leads to an increased susceptibility to loss of function, disease, and death. Aging is the major risk factor for many chronic and fatal human diseases, including Alzheimer's disease, multiple cancers, cardiovascular diseases, and type 2 diabetes mellitus (T2DM), which are collectively known as age-related diseases (ARDs). However, genetic, environmental, and pharmacological interventions can ameliorate loss of function during aging and confer resistance to multiple age-related diseases in laboratory animals. Age-related multimorbidity, the presence of more than one ARD in an individual, is posing a major and increasing challenge to health care systems worldwide. An important, open question, therefore, is whether mechanisms of aging in humans contribute to multimorbidity in patients, and hence whether intervention into these mechanisms could prevent or treat more than one ARD simultaneously.
Specific biological mechanisms begin to fail as an individual ages. Individual aging hallmarks are present in the development or disordered physiology of specific ARDs. For example, loss of proteostasis appears to have a prominent role in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, which are associated with protein aggregates composed of amyloid-beta and α-synuclein, respectively.
The role of genes in individual human ARDs and ARD multimorbidity has been studied extensively, as has the link between aging hallmarks and individual ARDs. For example, previous studies have demonstrated that multiple, individual human ARDs share gene ontology (GO) terms linked to mechanisms of aging, specifically aging hallmarks. However, whether these underlying mechanisms of aging contribute to the occurrence of multimorbidity in patients has not previously been investigated. Here, we explore the notion that the same aging hallmark may contribute to risk of multiple ARDs and, therefore, results in their co-occurrence in the same individual (i.e., ARD multimorbidity).
To address this question, we text mined 917,645 literature abstracts followed by manual curation, and found strong, non-random associations between age-related diseases and aging mechanisms, confirmed by gene set enrichment analysis of genome-wide association study data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients.