Mechanisms of development of multimorbidity in the elderly

Abstract

In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K-AKT-mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation ("inflammaging"). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted. @ERSpublications Multimorbidities share many common underlying mechanisms that may be linked to common causes such as oxidative stress

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…This leads to a reduction in the key antiaging molecule sirtuin-1, which is reduced in the lungs of patients with COPD (Rajendrasozhan et al, 2008;Nakamaru et al, 2009). The same PI3K-mTOR pathway may also lead to the comorbidities associated with COPD, such as ischemic heart disease, type 2 diabetes, osteoporosis, chronic renal disease, and dementia (Barnes, 2015a). For example, endothelial progenitor cells, which are important for repairing damage to endothelial cells to maintain normal vascular function, show accelerated aging and decreased sirtuin-1 due to activation of PI3K (Paschalaki et al, 2013).…”

Understanding age-related diseases: report of the 2015 Ageing Summit

“…Secondly, histone proteins regulate the chromatin structure and thereby the level of gene transcription. Histones generally decline by number with ageing and changes in histone acetylation, methylation or phosphorylation may further account for the looser, more transcriptionally active chromatin structure with ageing [7]. In addition, sirtuins (type III histone deacetylases) have been associated with ageing, COPD, IPF and neurodegenerative diseases [13][14][15].…”

“…vitamin D deficiency) are highly prevalent in patients with COPD. Therefore, COPD patients might rather benefit from a healthy diet rich in fruit, vegetables and antioxidants to activate anti-ageing processes (sirtuin 1), than from sole caloric restriction [7].…”

“…However, in senescent subventricular zone neural cells, which had an extremely long cell cycle and slow proliferation rate, the H2AX phosphorylation was primarily related to DNA repair. A better understanding of the different histone modifications in age-related diseases (including the reduced histone deacetylases in COPD) is required before selective inhibitors of histone modification enzymes currently under development, can be used successfully [7].…”

“…Telomere shortening is accelerated in age-related diseases including cardiovascular disease, diabetes, pulmonary fibrosis and COPD [4,7]. In addition, Gabriele Saretzki (Institute for Ageing and Health, Newcastle, UK) examined the protective role of TERT in brain ageing and neurodegeneration [8].…”