We have discussed progressive deterioration of overall health as the defining aspect of the aging process, distinct from disease. In turn, the hallmarks describe prominent mechanisms that, when failing, lead to the manifestations of aging. But how do we connect the two? Here we argue that the so-called hallmarks and their interactions represent the main line of defense or response mechanisms that protect the organism against thermodynamic or other insults, and these defense mechanisms might be infinite. However, we propose that they all converge into a common outcome: a loss of molecular resilience. We will further argue that the loss of molecular resilience serves as a transducer that relays changes in molecular or cellular hallmarks into physiological outcomes as defined by the construct of intrinsic capacities [10]. This view suggests that the rheostat, or most central driver of aging is not to be found among the hallmarks, but rather, it is the loss of systems biology-level interaction among the hallmarks that leads to a loss of resilience, and this is the central, defining characteristic of the aging process, itself leading to frailty, age-related disease, and ultimately death.

To begin, let’s clarify that the term resilience is used here within the context of the molecular and cellular changes that occur as a response to a given physical, chemical, or biological stress, as opposed to psychosocial challenges. As such, we are talking about “molecular resilience,” that is, the capacity present in every cell in our organism to respond, recover or adapt to a molecular or biological challenge, be it UV radiation, chemotherapy, a virus, or any other physical challenge [11]. Importantly, resilience is an active and dynamic process of the organism interacting with the environment, and this differentiates it from frailty, which is a passive state of physiology.

The focus on resilience might seem arbitrary. After all, while it is clear that in older people the loss of resilience results into a precipitating decline in health, we usually accept that we die of age-related chronic diseases and/or frailty. In fact, there is a clear interplay between resilience, frailty, and disease, whereby any of these processes can exacerbate and accelerate the development of the others, and either the loss of resilience or the development of severe disease can initiate the downhill trajectory towards frailty and death (Fig. 1).

Why focus on resilience then? For one thing, while any given age-related disease only affects a small fraction of the population, loss of resilience—and later, frailty—happens to every individual in virtually all species, usually starting in early adulthood. Perhaps more importantly, at the population level the loss of resilience temporally precedes frailty and age-related chronic disease by several decades, and because of that very reason, unraveling the role and mechanisms of resilience loss will provide an earlier window on which to intervene. As an example, world records in any sports decline with age, in spite of the fact that the practitioners involved are master athletes at the top of their game; but performance at the top of the game is dependent on age [12]. This is depicted in Fig. 2, using world record speed in 100-m dash at different ages. While we recognize that record speed in a sprint is not truly a measure of resilience, we use it here as a proxy since currently there are no widely accepted methods to ascertain resilience (see below). While Fig. 2 shows a decline in record speed already in the 30 s and 40 s, the appearance of frailty is not truly significant at the population level until around 70 years of age. Similarly, the increased incidence of age-related diseases such as coronary artery disease is not evident until a significant loss in resilience has occurred, at which time genes and environment can act upon the “weakened” (that is, less resilient) individuals. Finally, the increase in frailty occurs at a very late age in most individuals, probably due to a strict ceiling effect in its definition [21].

The timeline of appearance of resilience loss, frailty and age-related disease. Loss of resilience, represented by the world record speed in 100 m races at different ages (circles, ref. [12]) precedes both the appearance of disease (squares, ref. [20]), and appearance of frailty (triangles, ref. [21])

We therefore propose that loss of resilience might represent the composite end-result of molecular declines in any of the multiple processes that we know as the hallmarks of aging. We posit that, due to differences in genetic and environmental clues, loss of resilience might be driven by a different molecular/cellular aging process in any given individual, but since the biological processes represented by the hallmarks of aging heavily interact with each other, the end-result is a generalized loss of resilience, which is independent of the initial trigger. In other words, while some individuals might start their decline because of poor proteostasis, others might do so because of accumulation of senescent cells, or a decline in any of the other aging-related processes. However, because of their interdependencies, the end-result is always the same: a decrease in the ability of the organism to respond and recover from a stress, or in other words, a loss of resilience. Furthermore, in addition to each individual displaying different susceptibilities to each hallmark of aging, individuals also differ in the way their organism might respond to the ensuing loss of resilience, so that once the process starts, again there is a variety of physiological process that can be affected, and each individual will be affected by the loss of resilience in a unique manner, again driven by their individual genes and environment. As a result, each individual might present a primary decline in a different functional capacity, depending on their own genetics and environment.

In summary, we propose that a decline in function within any of the hallmarks of aging will result in a generalized decline of the entire molecular and cellular network, leading in all cases to a decline in resilience, which in turn will compromise all aspects of intrinsic capacities, leading to frailty and disease. However, the predominant phenotypic manifestation of this decline, such as decreased mobility or declining cognition, will again depend on the individual’s genes and environmental/behavioral exposures. As such, we propose that the loss of resilience represents a nexus or transducer that links the biology of aging to the loss of function and health represented by loss of intrinsic capacities (Fig. 3).

The central role of resilience as a transducer of information. Loss of resilience acting as the key transducer of information from the molecular and cellular drivers (the hallmarks of aging) to their consequences in terms of physiological (and pathological) outcomes, represented by changes in Intrinsic Capacities