Inflammaging, a Common Factor in the Development of Sarcopenia and Metabolic-Associated Liver Disease (MAFLD)

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, with its prevalence increasing annually. This condition is interlinked with signs of metabolic syndrome including obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and atherogenic dyslipidaemia. Importantly, moderate alcohol consumption frequently coexists with NAFLD individuals who present clinical features of alcohol- and metabolic-associated steatohepatitis, thus displaying a DUAL etiology. The term metabolic-associated liver disease (MAFLD) has recently replaced NAFLD since it reflects more accurately the pathophysiology of the disease, including metabolic dysfunction rather than the absence of alcoholism, and avoids diagnosis mistakes between Alcoholic Liver Disease (ALD) and NAFLD, taking in consideration that both can coexist in a patient [1]. The incidence of MAFLD has been described to be around 25% in the adult population, being the most common chronic liver disease, and it is expected to continue growing until 33.5% in 2030, with a tremendous socio-economic impact since it is well-known that MAFLD increases the risk of systemic diseases and mortality [2].

In elderly people, MAFLD prevalence is high, representing approximately a 40.3% among 60–74 year-old individuals and 39.2% in people over 74 years, commonly associated with a higher risk of death especially in the 60–74 group [3]. In this age group, the elevated incidence of MAFLD can be explained for the common presence of triggering factors for MAFLD development including hypertension, T2DM, hyperlipidemia, and obesity. MAFLD in elderly patients can have serious consequences. For instance, it is well documented that, one year after diagnosis, MAFLD can progress to cirrhosis, liver transplant, or hepatocellular carcinoma (HCC) in 9% of senior patients, and after 8 years up to 39% will be affected with at least one of these liver conditions [4].

Recently, it has been reported that MAFLD is tightly associated with sarcopenia development in older adults [5]. The European Working Group for Sarcopenia in Older People has defined sarcopenia as a syndrome characterized by a progressive and generalized loss of skeletal muscle mass and strength, with a high risk of developing physical incapacity, bad quality of life, and death [6]. Around 15% of people between 65 and 80 years old, and more than 50% of senior citizens over 80, manifest sarcopenia, which compromises their autonomy [6]. Sarcopenia can be present in early stages of chronic liver conditions and worsens with the severity of the liver disease [5]. For example, in middle-aged men, sarcopenia affected 8.7% of subjects without MAFLD, 17.9% of patients with MAFLD, and 35% of patients with non-alcoholic steatohepatitis (NASH) [7]. The link between the liver and muscle in the context of MAFLD is further supported with data showing that individuals with lower muscle mass have an increased risk of developing MAFLD [5]. Additionally, a study that followed more than 13,000 patients with or without MAFLD for a period of 7 years showed that increases in muscle mass over time could prevent the development of MAFLD or even promote the resolution of existing MAFLD [8]. Moreover, the presence of significant liver fibrosis was reported to be higher in people with sarcopenia compared to those without this condition [7]. These data strongly suggest that sarcopenia is a common factor in MAFLD patients and muscle mass retention could reduce the risk and severity of MAFLD.

However, the molecular mechanisms underlying the pathophysiology of the liver–muscle crosstalk remain unknown. A possible culprit has been identified: Inflammaging, a characteristic inflammation developed during the old age. Inflammaging is a chronic and low-grade inflammation associated with aging, present in the absence of an active infection and primarily driven by endogenous signals [9]. A similar chronic low-grade inflammation is activated in the context of high nutrient intake and obesity, and this metabolic-related inflammation is indicated to be involved in the development of insulin resistance in organs such as the liver, adipose tissue, and muscle and, certainly, in the pathogenesis of MAFLD [10]. Actually, low-level chronic inflammation and triglyceride accumulation in the liver are considered the main factors that trigger MAFLD [10]. The inflammation affecting the liver comes from several sources, such as: Adipose tissue secretion of inflammatory factors (mainly pro-inflammatory cytokines), secretion of inflammatory factor by resident macrophages (Kupffer cells) and infiltrated immune cells in the liver (Th1 and Th17 lymphocytes, M1 macrophages), and as a consequence of inflammation in the gut and in the muscle [10]. It has been proposed that the liver is not the initial organ responsible for the development of inflammation during obesity, but it helps to maintain and reinforce inflammation once established, leading to more serious conditions such as NASH [10].

The above-described course of events is not that different in sarcopenia, where inflammaging is also involved in the pathogenesis of the syndrome [9]. Different stimuli that disturb immune system homeostasis can induce inflammaging, including virus infections (such as cytomegalovirus), bacterial infections (as in periodontitis), misfolded or oxidized proteins, gut dysbiosis, and metabolic dysfunction [9]. The skeletal muscle is particularly sensitive to a chronic inflammation, even to a low-grade one, where different pathways that regulate protein catabolism, such as ubiquitin/proteosome, calpains, autophagy and apoptosis, can be perturbed by inflammation potentially causing muscle loss [11]. Protein synthesis appears to be affected too, because an ’’anabolic resistance’’ is observed in sarcopenic animal models and patients, where under anabolic stimuli as amino acid intake, resistance exercise or insulin, protein synthesis is not activated [11]. The common pathogenesis between MAFLD and sarcopenia can be seen in middle-age and old patients with MALFD who lose muscle mass and strength in a process known as sarco-obesity. We can propose that low-grade chronic inflammation related to metabolic or age-related immune system alterations may synergistically potentiate the development of MAFLD and sarcopenia among older adults.

Another open question is how retention of muscle mass can be considered a novel therapeutic avenue for MAFLD. Skeletal muscle can be an endocrine organ, capable of secreting hormones known as myokines to the bloodstream, which can have physiological effects over distant organs, such as the liver (crosstalk known as muscle-liver axis) [12]. A plausible factor for MAFLD development could be the perturbation in myokine secretion as a consequence of the reduction in muscle mass. For example, myostatin, a well-known myokine, inhibits muscle growth, and its inactivation in animal models reduces fat deposition in the liver. Moreover, myostatin may also decrease human stellate cell activation and proliferation, and it can be highly elevated in end-stage liver disease patients [13]. Irisin is another myokine, derived from the proteolysis of the transmembrane protein FNDC5, that is secreted to the blood mostly during and after exercise [12]. Downregulation of FNDC5 caused an increase in steatosis, insulin resistance, and apoptosis in response to inflammation in primary hepatocytes. Lower levels of irisin in blood in MAFLD and NASH patients may be also a sign of muscle–liver axis alteration, but these findings need further investigation [13]. Apelin, also a myokine, which reduces insulin resistance and fat storage in adipocytes, may have protective effects over liver steatosis as well [13].

Altogether, we can conclude that analysis of the skeletal muscle health should be performed in all patients with chronic liver diseases. Therefore, it is plausible to suggest that promoting strategies to favor muscle mass increments in patients with MAFLD could have therapeutic benefits. To study the common molecular mechanisms behind MAFLD and sarcopenia, today vastly unknown, and understand the relationships of the muscle-liver axis in a physiological and a pathophysiological context, will have profound effects on the pharmacological and non-pharmacological actions against MAFLD and sarcopenia, both debilitating conditions affecting the elderly.