Frailty and the aging male

Abstract

Frailty occurs in aging males for a variety of reasons. It is less common in males than females. Diseases which are particularly associated with frailty are diabetes mellitus, atherosclerosis, anemia and chronic obstructive pulmonary disease. Insulin resistance syndrome plays a pathogenetic role in the “fat-frail” syndrome. Sarcopenia occurs predominantly because of hormone deficiency and cytokine excess. Pain and anorexia are also associated with frailty. Stem cell research represents a potential promise for the treatment of frailty.

Keywords:

• Sarcopenia
• myostatin
• IGF-1
• testosterone
• cytokines

Introduction

Over the last decade there has been an increasing enthusiasm to understand the pathophysiology of frailty and potential approaches to its prevention. Frailty represents a syndrome that is easily recognizable by most clinicians but has proved difficult to define. Frailty can be considered as a syndrome when deterioration in a person's basic physiological mechanisms places them at increased risk for developing disability, even when exposed to a minor degree of stress. Attempts to objectively define frailty have been fraught with difficulty. Recently, the definition of Fried et al. [1] has been widely accepted as a working model (Table I). This definition is predictive of subsequent disability and mortality [2]. Using this model, the prevalence of frailty is 6.7%, with females being more likely to be frail than males. This is in keeping with the well-recognized phenomenon that while females live longer than males, males spend less of their life with a functional impairment than do women.

Table I. Objective definition of frailty^* as proposed by Fried et al. [1]

	Parameter	Frailty Indicator
1.	Weight loss	>10 lbs weight loss in one year
2.	Grip strength	Lowest 20% of population
3.	Exhaustion	Self report
4.	Walking speed	Lowest 20% of population
5.	Low activity	Males < 383 Kcals/week
		Females < 270 Kcals/week

^*Frailty is defined as having three or more of the above criteria.

The reason(s) for males being less likely to become frail over their lifespan is multifactorial. Firstly, males tend to have a higher peak bone mineral density and muscle mass. Also, there is a suggestion that males have a slower rate of loss of muscle and bone. The possible reasons for this are unclear but can include a tendency for males to do more recreational exercise than females. Increased arthritis and pain syndromes in females lead to disuse of muscles or genetic factors. When examining world records for athletic events over the lifespan, females show an accelerated rate of decline compared to males, supporting the greater rate of physiological decline in females compared to males [3].

The causes of frailty are multifactorial. They include pain, diseases such as congestive heart failure and diabetes mellitus, alterations in central nervous system function, poor nutritional intake and physical inactivity. Many of these conditions lead to deterioration in the VO₂max, making it an excellent measure of physiological compared to chronological aging [4]. Many of the physiological deteriorations produced by disease processes are mediated by proinflammatory cytokines. Physiological deterioration also occurs due to the decline in hormones, such as testosterone, and insulin growth factor-1. An overview of the factors involved in the pathophysiology of frailty is given inFigure 1. Recently, it has been postulated that the insulin resistance syndrome is a key factor in the pathogenesis of frailty [4],[5].

Figure 1. Factors involved in the pathophysiology of frailty.

Of worms and frailty

The nematode, Caenorhabditis elegans, has a decrease in its body movement over its lifespan [6]. This decline in body movement is related to muscle deterioration [7]. This muscle deterioration resembles that which is histologically present in humans with sarcopenia. There is no deterioration in neurons. This decline in older animals is associated with an impairment of the behavioral response to sensory cues and is a predictor of lifespan [8]. Overall, these studies suggest that worms can be utilized as a model of frailty and functional deterioration.

Diseases and frailty

Atherosclerosis leads to a variety of diseases associated with frailty including congestive heart failure, peripheral vascular disease and cerebrovascular accidents. In males, erectile dysfunction has been shown to be a predictor of future cardiovascular disease [9]. Atherosclerosis is associated with increased levels of cytokines, in themselves a factor involved in the pathogenesis of frailty. Fried et al. [1] originally created their objective definition of frailty in persons with heart disease. Persons with congestive heart failure have a decline in cardiac output leading to a reduction in endurance capacity and, often, peripheral muscle wasting. This is particularly true in those persons who develop cardiac cachexia [10]. While drugs that block angiotensin-converting enzyme activity appear to improve muscle strength [11], many of the drugs used to treat heart failure may increase frailty. Recently, there has been an increased awareness that furosemide may lead to increased weakness, orthostasis, dehydration, worsening frailty and mortality.

Persons with chronic obstructive pulmonary disease (COPD) have a poor VO₂max. They have elevated levels of cytokines. Hypoxia decreases the function of both muscles and the brain. Testosterone levels are often extremely low in persons with COPD [12]. Testosterone replacement improves strength and function in patients with COPD [13-15].

Anemia has been shown to be related to frailty, falls and functional decline in older persons [16],[17]. Even when the hemoglobin is between 10 g/dl to 14 g/dl there is an increased functional decline. Erythropoietin and its analogs can enhance function.

The disease par excellence that leads to frailty is diabetes mellitus. Diabetic patients have elevated cytokines, low testosterone levels and accelerated atherosclerosis [18]. Depression further leads to problems in persons with diabetes mellitus [19]. Numerous studies have shown that diabetics have excessive decline in function and an increased propensity to have injurious falls [20-22]. The AWARE study demonstrated that older diabetics are much less capable of carrying out higher-level functions such as reading and gardening [23] (Figure 2).

Figure 2. Diabetics show increased problems doing daily quality of life functions.

Insulin resistance syndrome and frailty

Middle-aged men with visceral obesity are particularly prone to develop the insulin resistance syndrome [5]. The hyperinsulinemia that occurs in conjunction with insulin resistance leads to hypertension, hyperglycemia, hypertriglyceridemia, low HDL cholesterol, increased uric acid, abnormalities in coagulation factors, non-alcoholic steatotic hepatitis (NASH), myosteatosis (fat infiltration in muscle) and cognitive dysfunction (Figure 3). Persons with this syndrome also have leptin resistance related to the hypertriglyceridemia [24]. The hypertriglyceridemia also appears to play a role in the development of the myosteatosis and the cognitive dysfunction. Insulin resistance plays a pathogenetic role in the “fat-frail” syndrome.

Figure 3. Intracellular effects of IGF-1 on muscle growth.

Sarcopenia, cytokines and hormones

Sarcopenia is the excessive loss of muscle mass. Sarcopenia occurs in 8.8% of young-old women, compared to 17.5% of old-old men [25]. Persons with sarcopenia have an increase in functional decline. Obese persons with sarcopenia have the highest functional decline and mortality.

C-reactive protein, a nonspecific marker of cytokine excess, is related to loss of muscle mass and strength [26]. Interleukin-6 has been termed the “geriatric cytokine”. Elevated levels of it and interleukin-2 are associated with loss of muscle mass, strength and function [27]. Cytokines not only cause loss of muscle mass by inhibiting the NF-kappa-B system and activating the ubiquitin-proteasome system, but also modulate the immune system, decrease circulating albumin levels, produce anemia and anorexia, decrease cognition, enhance lipolysis and inhibit lipoprotein lipase, leading to hypertriglyceridemia and to sickness behavior. This has lead to the concept that there is a cytokine related aging process [28].

Three hormones appear to play a major role in the pathogenesis of sarcopenia in males. These are testosterone, vitamin D and the muscle isoform of insulin growth factor-1. Testosterone levels decline with aging at the rate of 1% per year [29],[30]. Because of the increase in sex hormone binding globulin available to the tissue, hormone levels decline to an even greater extent. The decline in testosterone levels has been correlated with a decrease in muscle mass and strength [31], and in one study with a decline in function [32]. Testosterone administration to hypogonadal older males increased muscle strength [33],[34], and in persons who are borderline hypogonadal it increased muscle mass [35]. Two small studies have suggested an improvement in function after testosterone administration [36],[37]. The effects of testosterone on muscle are listed inTable II. The role of testosterone in the prevention and treatment of frailty requires large, multicenter trials to prove its utility.

Table II.  Effects of testosterone on muscle

• Testosterone increases muscle size and type I and type II fibers

• Testosterone enhances muscle synthesis

• Testosterone increases satellite cell precursors and inhibits adipocyte precursors

• Old and young muscles respond similarly to testosterone

Vitamin D levels have been shown to decline with aging [38]. Low vitamin D levels are associated with functional deterioration and falls [39]. Vitamin D replacement enhances muscle strength and function in persons with low vitamin D levels, but not in those with normal levels [40].

The muscle isoform of IGF-1 appears to be particularly important for the maintenance of aging muscle. The insertion of the transgene for the muscle isoform of IGF-1, into older rats, resulted in the reversal of muscle mass loss [41]. The intracellular mechanisms by which IGF-1 controls muscle growth are shown inFigure 3.

Myostatin D inhibits muscle growth. Inhibition of myostatin D leads to muscle hypertrophy [42]. The role of myostatin D in sarcopenia is unknown. The other causes of sarcopenia include decreased neuronal stimulation of the muscles, decreased blood flow, decreased physical activity and a decrease in nutrient intake. There is some evidence that the intake of creatine may be particularly important for older muscles [43-45].

Anorexia of aging and frailty

A physiological anorexia of aging occurs over the lifespan [46]. Males develop a greater physiological anorexia than do females. This is due to the decline in testosterone levels in males leading to an increase in leptin. This physiological anorexia places the older male at an increased risk of developing malnutrition when they develop a disease process. Weight loss leads to institutionalization, hip fracture and death in older persons [47].

A number of diseases are associated with a large increase in cytokine burden. This leads to marked loss of muscle and fat. This syndrome is called cachexia. Inadequate ingestion of calories and micronutrients can also lead to anemia and cognitive decline.

Pain

Pain is considered the fifth vital sign. Pain is very common among older persons and is often not treated [48]. Pain can lead to disuse atrophy and contractures. Pain often limits the amount of physical activity an older person will undertake and limits involvement in exercise programs. Treatment of pain leads to enhanced response to resistance exercise [49].

Central nervous system function and frailty

Dementia is not necessarily associated with frailty [50]. Many demented males maintain strength and activities until near the end of the disease. The end stage of Alzheimer's disease is associated with some alterations in neuronal muscular function. Persons with Parkinson's disease and with vascular dementia often develop frailty early in the course of the disease.

Balance deteriorates along with the aging process. Poor balance is associated with an increase in falls and a fear of falling [51]. Both of these can lead to frailty. Balance exercises can reverse the deterioration in balance and slow the development of frailty. In animals, enhancing the environment can improve balance and produce new neuronal growth [52]. Alterations in the beta-adrenergic input of the cerebellum play a major role in the age related loss of balance [53].

Persons with depression have a decreased motivation to undertake exercise and can develop a pseudodementia [54]. They also have an increased propensity to develop myocardial infarction [55] and have poor outcomes associated with rehabilitation [56]. Depression increases corticotrophin releasing factor, which leads to anorexia and an increase in muscle wasting [57]. All of these factors make depression a major factor in the pathogenesis of frailty.

Conclusion

Frailty is a complex condition representing pre-disability. It has multiple causes. Although it is less likely for males over the lifespan to become frail, when compared to females, early recognition of frailty and its aggressive treatment should slow the onset of functional deterioration. Resistance exercise is the cornerstone of the management of frailty. There is a need to intensively study the role of hormone replacement (testosterone and vitamin D) in the treatment of frailty. Stem cell research represents a potential promise for the treatment of frailty.