Chronic Liver Disease Produces Accelerated Epigenetic Aging in Other Tissues – Fight Aging!
Our organs and bodily systems are all interconnected. Organ A relies on organ B in some way for many combinations of A and B and specific functions of those organs. Thus when an individual suffers from some form of age-related chronic disease, in which the function of one organ is particularly disrupted relative to all of the others, the whole body tends to suffer. This is one of the reasons why the research community observes correlations between the incidence of many different age-related diseases that occur in different organs.
As an example of this point, in today’s open access paper researchers deploy epigenetic clocks to show that patients with chronic liver disease exhibit accelerated epigenetic aging in other tissues. The liver is the center of lipid metabolism in the body, and manages the blood-carried levels of many molecules that are important to the function of other organs. Separately, the liver also detoxifies a range of metabolic waste and foreign molecules that find their way into the digestive system and bloodstream. Faltering in these tasks has consequences.
Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease
Chronic liver disease (CLD) is a debilitating proinflammatory ‘scarring’ condition that often results in the development of age-associated comorbidities (especially physical frailty), leading to reduced quality of life and ultimately increased mortality. Increased systemic inflammation is recognized as a key driver of the aging phenotype, which increases the risk of multiple life-limiting diseases. The present study investigated whether CLD increases the rate of biological aging in skeletal muscle and in the immune system. These biological systems with known hallmark mechanisms of aging were also investigated to help explain the increased incidence of sarcopenia and reduced immunity in this patient population.
Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years). Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge, DunedinPACE, or Hannum epigenetic clocks, with no difference using the Horvath clock. The present findings provide the first evidence of increased biological aging in patients with CLD across these two biological systems utilizing epigenetic and immune phenotype-based measures. Clinically, the identification of a divergence of biological age from chronological age, or the presence of a negative aging trajectory, may highlight CLD patients at greatest risk of disease progression, allowing early therapeutic intervention, including medicines that directly modulate aging processes.
It has previously been reported that patients with CLD display hallmarks of aging, including reduced telomere length in liver tissue, hepatocytes, and leukocytes, and this telomere attrition is positively associated with mortality risk and hepatic fibrosis. In line with this, the present study identified greater epigenetic age acceleration in the skeletal muscle tissue of CLD patients, suggesting that epigenetic muscle aging may be a contributing factor to the development of muscle dysfunction, which has been reported in up to 70% of patients with CLD. Aging is also associated with a chronic increase in circulating proinflammatory cytokines and a decrease in the level of anti-inflammatory cytokines, a process referred to as ‘inflammageing‘.
Although the mechanisms that drive age-related epigenetic changes are not fully understood, elevated levels of circulating factors, including proinflammatory cytokines, such as TNFα, IL-6, and IL-12, may play a role in modulating epigenetic modifications of DNA. Similarly, increased adiposity, which is also strongly associated with chronic low-grade inflammation, has been reported to drive epigenetic age acceleration in other tissues, including the liver. Therefore, it is possible that alterations in circulating factors, such as increased levels of proinflammatory cytokines or ammonia following primary liver dysfunction, may drive epigenetic changes in secondary tissues, such as skeletal muscle, negatively impacting their aging trajectory. However, it will be important to elucidate key factors that drive epigenetic aging and those that become elevated secondary to age-associated changes in cellular function.
