Understanding frailty.

255 The report of Linda Fried and colleagues (1) in this issue extends and complements their consecutive effort to build a rigorous conceptual framework of frailty. The importance of the topic and its general lack of address endorse the significance of these data. For me, the most important new insight is provided by the authors’ strong suggestion that the nonlinearity of the multiple system defects presumes the involvement of a complex system. Like the weather, the Internet, and even health, frailty resists facile measurement and definition. Fried and colleagues have done much to change this. Their measurement of six specific systems concludes that the frailty phenotype is related to the numbers of defects, but not the particular type of system involved, and further is independent of chronological age. These data add a further dimension to the formulation. The syndrome of frailty derives not from singular components of the system but from the system as a whole. As such, frailty, like the weather, Internet, and health, qualifies as an emergent construct (2). “emergence” is defined as a state that derives its essence from the multiple synergies of the components—not from the individual ones. As such, it is the reverse of reductionism. emergence has been around since Aristotle—“the whole is more, sometimes much more, than the sum of its parts. ” Julian huxley observed, “now and again there is a sudden rapid passage to a new and more comprehensive type of order or organization with quite new emergent properties and involving quite new methods of further evolution (3). ” More recently, in a signal Science article, physicist Philip Anderson declared, “More is different (4). ” By this, he insists that comprehension of each hierarchical level requires assay of that specific level. Knowledge obtained from the levels above and below does not suffice. This approach is rendered current too by the recent recognition that the organism is not defined by the component genes themselves or even by them in the aggregate, but in the way that the gene ensemble interacts with the environment in a discipline known as epigenesis. This rubric has been called “the epicenter of modern medicine” by Feinberg (5). Asserting that frailty qualifies as an emergent state connotes other important differentiating aspects. Not only is the organism not comprehended by summing its parts, it is encompassed only by the addition of a time dimension. Frailty can be understood as a process—not merely as a frozen moment. Our neocentric fixation always struggles with time. Richard Dawkins (6) points out how even einstein had difficulty in reconciling time with his formulations. The insertion of a time dimension in our understanding of frailty introduces the important process of phenotypic plasticity . The details of how the organism conforms its structure to a particular environmental field is now known in great precision. In a real sense, “it becomes what it does (or doesn’t). ” Such plasticity over time is the result of differential gene expression. The article of Fraga and colleagues (7) showed that the gene portrait of identical twins at birth is virtually identical. But with the passage of time, the phenotypes become progressively more distinct. Such divergence is the probable explanation for the recognized heterogeneity of older people. The “use it for lose it” idiom restates phenotypic plasticity. The process, newly termed “symmorphosis” by Weibel, reveals why multiple functions, exposed to a common environmental signal, scale quantitatively with one another, negating a rate-limiting step (8). Symmorphosis also explains why fitness is a general widely distributed anabolic feature and why frailty is similarly catabolic and system-wide in its expression. Symmorphosis is, in a sense, a tautology proposing that like all boats in a harbor responding in a similar matter to a tidal change, so too do the multiple interconnected gene networks react in concert with the energetic field in which they exist, and their form in time reacts in the scaled fashion. Weibel utilizes the two major energy substrates of oxygen and fuel to illustrate the concept. VO2 Max, for example, is a basic functional expression of how an organism extracts oxygen from the atmosphere and conducts it to the mitochondria to facilitate metabolism. Its conduits involve multiple transport steps representing respiratory, circulatory, cell membrane, and metabolic enzyme content. Data indicate that each individual step of this transport reacts in a quantitatively linked fashion to the energy field. From this example, it implies that the anabolic and catabolic processes of cell, tissue, and organ reflect the energetic fields. Such a proposal can be considered as an emergent property. The diverse states of immobility and malnutrition are prime causative agents of frailty. This recognition compels the reality that adequacy of energetic stimulus is a base requirement imposed by nature. We recognize that the matter of life interfaces with the twin agencies of time and energy. editorial