Recently, we and others proposed that while agreeing on an operational definition of frailty is very important for translational purpose, until the pathophysiology of frailty is fully understood, any operational definition of frailty should be considered temporary and amenable to change. Importantly, the theoretical discussion and research on the biological and mechanistic origin of frailty does not completely depend on a specific operational definition. We recently proposed an agnostic approach, which assumes that frailty is, in fact, a syndrome of accelerated aging and, therefore, phenotypes of aging as well as frailty can be identified as those physiologic dimensions that change with aging in all humans and, perhaps, in all living organisms. For example, the risk of developing a clinical disease such as coronary artery disease (CAD) increases with aging but not all individuals develop CAD. Therefore, CAD cannot be considered a phenotype of aging. On the other hand, percent body fat, especially visceral fat, increases with aging in all individuals and, therefore, increased visceral fat could be considered a phenotype of aging. Based on these assumptions, we proposed that the phenotypes of aging can be clustered in discrete interactive domains, whose impairments are pervasive across body systems and, therefore, can serve as proxy measures of the rate of aging. In particular, we identified four main “aging phenotypes” that we hypothesize are closely related to frailty and late-life decline: (1) signalling networks that maintain homeostasis; (2) body composition; (3) balance between energy availability and energy demand; and (4) neurodegeneration/neuroplasticity, whose changes occur in parallel in all aging individuals and are strongly intercorrelated (Figure 46-5). Extensive evidence, in fact, shows that frailty is associated with overt changes in these four main interacting domains regardless of its operational definition. Such conceptualization of frailty also recognizes the heterogeneity and dynamic nature of the aging process. Aging is a universal phenomenon, but the progressive multisystem instability and deterioration that characterize aging are very heterogeneous among different individuals. Thus, not only whether an older patient is frail, but also whether the severity of the frailty syndrome is beyond clinical and behavioral thresholds becomes relevant. Furthermore, the conceptualization of frailty as a result of various levels of impairment in the “aging phenotypes” represents an interconnecting and dynamic interface between the clinical presentation of the syndrome (first layer of frailty) (see Figure 46-2) and its biological bases (the inner and deeper layer or biological core of frailty). This model provides a causal link to the development of multiple chronic diseases and geriatric syndromes, whose occurrence can be interpreted as clinical expression of alterations in specific combinations of aging phenotypes.
Schematic representation of the domains of the aging phenotype, and their relationship with frailty and with the geriatric syndrome. (From Ferrucci L, Studenski S. Clinical problems of aging. In: Longo DL, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012.)
Signalling Networks That Maintain Homeostasis
A remarkable and pervasive biological feature of aging and frailty is the presence of a chronic and mild proinflammatory state, revealed by elevated levels of serum proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Such a proinflammatory signature of aging, also called “inflammaging,” has been described across different animal models and tissues, and is even present in individuals who are free of diseases, disabilities, and cardiovascular risk factors (Ferrucci et al., 2005). Moreover, higher levels of proinflammatory biomarkers have been associated with loss of physiologic reserve and function across multiple organs and system in older adults. These biomarkers are strong independent predictors of adverse health outcomes including multiple chronic diseases, disability, hospitalization, and mortality.
Research on the biology of aging has shed some light on the underlying mechanisms of the proinflammatory state of aging. For example, one of the possible triggers is defective autophagy, a fundamental cellular housekeeping mechanism that eliminates altered macromolecules, cell membranes, and organelles before they are replaced. In particular, the processing and elimination of aged and degraded mitochondria appears to be impaired. These dysfunctional mitochondria cannot be replaced, are energy inefficient, and produce large quantities of radical oxygen species which are supposed to trigger a chronic inflammatory response. Animal models demonstrate a strong connection between the accumulation of senescent cells and the development of characteristic aging phenotypes. One of the main features of senescence is the senescence-associated secretory phenotype that is characterized by the secretion of proinflammatory mediators, including IL-6 and IL-1, and may account for the proinflammatory state of aging.
An additional and relevant characteristic of the aging process is the occurrence of complex and profound hormonal changes, including a decline in multiple anabolic hormone concentrations (dehydroepiandrosterone sulfate [DHEAS], testosterone, estrogens, growth hormone [GH]/insulin-like growth factor 1 [IGF-1], and vitamin D), with a relative preservation of catabolic hormones (thyroid hormones, cortisol). A single hormonal alteration, in fact, is unusual in older persons and usually is a sign of a specific impending disease. More often, aging individuals experience a complex “multiple hormonal dysregulation,” characterized by simultaneous and synergistic mild multiple anabolic hormonal deficiencies, which may be an important contributor to progressive loss of resilience and high vulnerability in older adults. Multihormonal dysregulation has also been associated with the development of numerous geriatric conditions, including sarcopenia and cognitive decline as well as high risk of disability, comorbidity, and mortality.
Aging is also characterized by major changes in body composition which negatively affect metabolism and functional status. These changes contribute to impaired mobility, disability, and other adverse health outcomes in older adults. Lean body mass, composed predominantly of muscle and visceral organs, starts to decline progressively around the age of 30 with a more accelerated loss after the age of 60, while fat mass increases with age during middle age and declines in late life. Age-related loss of muscle mass is typically offset by gains in fat mass as adults age with resulting stable or slightly increasing body weight. After the age of 70, fat-free mass and fat mass tend to decrease in parallel, with consequent decreasing weight. Furthermore, visceral fat and intermuscular fat tend to increase with age, while subcutaneous fat in other regions of the body declines. The age-related loss of muscle mass, with a shift in muscle fiber composition, due to a selective loss in fast-twitch fibers compared to slow-twitch fibers, was long considered the major determinant of decline in muscle strength in older adults.
However, the decrease in muscle strength actually exceeds what is expected on the basis of the decline in muscle mass alone, especially after the age of 60 to 70, suggesting that other factors related to muscle quality (defined as muscle strength or power per unit of muscle mass) may play a major role in the decline in muscle strength and physical function in older adults. Muscle biomechanical quality, defined at the force that is generated by a volume unit of muscle tissue, is almost constant in children and young adults but starts deteriorating after the age of 40. Progressive muscle denervation secondary to progressive failure of the denervation/reinnervation cycle and to dysfunction of the neuromuscular junction is probably largely responsible for the decline of muscle mass and quality with aging. Furthermore, there is increased fat infiltration within the muscle, which probably results from age-related changes in body composition and includes storage of lipids in adipocytes located between the muscle fibers (also termed intramuscular fat) and between muscle groups (intermuscular fat) as well as lipids stored within the muscle cells themselves (intramyocellular lipids). This fat infiltration is thought to be largely responsible for the deterioration of muscle quality, impaired muscle force production, and mobility decline in older adults.
In addition, an increase of fibroconnective tissue within the muscle contributes to poor muscle quality with aging. Another focus is on the failure of mechanisms of the maintenance and repair of damaged muscle fibers, mainly due to the limited regenerative capacity and dysfunction of satellite cells (stem cells resident in muscle tissue), which may be exhausted before the end of life in situations that require continued and intensive repair. Overall, the decline in muscle mass and muscle strength with aging plays a critical role in the development of the frailty syndrome.
Progressive demineralization and architectural modification in the bone also occurs with aging, with consequent increased skeletal fragility and higher risk of fractures, especially at the hip. Trabecular bone mass “peaks” in early adult life, with decreases in trabecular bone evident in both sexes as early as the third decade, although the rate of decline is clearly accelerated in women compared to men.
Balance Between Energy Availability and Energy Demand
Although the idea that longevity and health are linked to energy metabolism was introduced over a century ago, the role of energy metabolism in human aging and chronic diseases is still not fully understood. As described earlier, Fried and colleagues conceptualized frailty as a vicious cycle of declining energetics and reserves. Indeed, the integrity of energetic metabolism is a prerogative for successful aging. In fact, the degenerative processes that characterize aging occur when the organism’s ability to balance energy production and expenditure declines. Lack of energy or even an excess of energy that is not utilized could be the root causes of progressively higher morbidity and mortality with aging. Resting metabolic rate (RMR) is the energy required to maintain structural and functional homeostasis at physical rest, in fasting and neutral conditions. RMR accounts for 60% to 70% of the total daily energy expenditure and can be assessed by indirect calorimetry. RMR normalized by body size declines rapidly from birth up to the end of the third decade, and then continues to decline more slowly from adulthood until death, mostly but not completely, as a consequence of the age-related loss of lean body mass.
In older adults higher RMR has been found to be an independent risk factor for mortality and to predict future greater burden of chronic diseases; consequently it should be considered a marker of health deterioration in older adults. Specifically, the increased RMR is likely to be due to increasing difficulties to cope efficiently and effectively with internal and environmental challenges and stressors. Therefore, in the presence of overt homeostatic dysregulation, the energy requirement increases because of the extra work required to maintain a stable homeostasis.
Moreover, the maximum energy that can be produced by an organism over extended time periods, or fitness, can be approximately estimated during a maximal treadmill test as peak oxygen consumption (VO2 max). Oxygen consumption represents the maximal ability to use oxygen to meet the energy demands of physical activity (maximal aerobic capacity) and reflects not only cardiovascular adaption to transport oxygen but also adaptations within muscle to use oxygen to meet the energy demands of physical activity. VO2 max declines with age, starting around age 30 and continuing at approximately 10% per decade, but at an accelerated rate for increasing age and in those who are sedentary or affected by chronic diseases. Of relevance, the age-related decline in maximal aerobic capacity is a strong predictor of decline in physical function and mobility in older adults.
An important biomarker of aging and frailty is the age-related degeneration of the central and peripheral nervous system (for details see Chapter 45). As result of these changes, declining performance in specific cognitive abilities, like memory, processing speed, executive function, reasoning, and multitasking is commonly experienced with aging. All of these so-called “fluid” mental abilities are important for carrying out everyday activities, living independently and leading a fulfilling life. In fact, there is a strong association between accelerated decline in cognitive performance and in mobility, even in “normal” older adults.
Age-related changes occur also at the level of the peripheral nervous system (PNS), especially after the age of 60, with a progressive degeneration in structure and function from the spinal cord motor neuron to the neuromuscular junction. These changes in the PNS greatly contribute to impaired mobility and decline in physical function in older adults. The number of motor neurons declines with aging and such declines seem to play an important role in the loss of muscle strength and quality with aging. Age-related motor unit remodeling leads to changes in fiber-type composition because denervation occurs preferentially in the fast muscle fibers with reinnervation occurring by axonal sprouting from slow fibers. As a consequence, motor units decrease in number and become progressively larger, but less functional with aging with reductions in fine motor control. Furthermore, the efficiency of segmental demyelination-remyelination process declines with aging, resulting in slower conduction of the impulses, with consequent decreased sensation as well as slower reflexes.