PERSPECTIVE https://doi.org/10.1038/s43587-020-00015-1 Asynchronous, contagious and digital aging Thomas A. Rando1,2,3 ✉ and Tony Wyss-Coray 1,3,4 ✉ Organismal aging is often characterized as a steady, monotonic decline of organ and tissue function. However, recent studies indicate spatial and temporal variations of aging rates across the lifespan. We consider these variations from the perspective of underlying cellular changes. Cells in certain tissues may age earlier and produce signals that accelerate the aging of other cells, locally or distantly, acting as drivers for organismal aging and leading to a lack of synchronous aging between tissues. As cells adopt new homeostatic states, cellular aging can be viewed, at least in part, as a quantal process we refer to as digital aging. Analog declines of tissue function with age may be the sum of underlying digital events. Cellular aging, digital or otherwise, is not uniform across time or space within organisms or between organisms of the same species. Advanced systems-level and single-cell methodologies will refine our understanding of cell and tissue aging, and how these processes integrate to produce the complexities of individual, organismal aging. volutionary theories of aging have sought to explain why we from features of cellular aging that might not have been predicted age, with concepts evolving over the decades from genetic from first principles. and deterministic to more physiological and adaptive theo- E1 ries . Among the most widely accepted theories currently are those Lifespan versus aging involving mutation accumulation, antagonistic pleiotropy and One of the reasons for a limited understanding of the determinants physiological trade-offs between the mortal soma and the immor- of individual aging is that the broader research field of aging and tal germline (Box 1)2–4. Such theories provide a basis for under- longevity has relied heavily on studies in model organisms in which standing aging as a result of processes whose manifestations are lifespan, and not aging itself, has been the predominant focus and subject to evolutionary selection for reasons other than aging primary benchmark. Studies of the determinants of lifespan within traits themselves. However, these theories shed little light on a species have been highly productive because of the numerous variations of the rate of aging within individuals of a species available short-lived model systems9,10, as well as the relative ease (Fig. 1). In this Perspective, we will discuss challenges to of the assay; namely, counting the number of animals that are alive the studies of aging and recent findings that highlight features versus the number that are dead. This has led to a growing list of of organismal aging that pertain to how individuals rather than genes, drugs and environmental factors (including diet) that can species age. influence the median and maximum lifespans of certain species11–13. Throughout, we will refer to aging as the underlying processes In contrast, the identification of the determinants that lead that lead to the cellular, tissue and organismal phenotypes associ- to an acceleration of aging in one member of a species and the ated with that phase of metazoan life known, in the vernacular, as slowing of aging in another has proved to be more challenging. old age. Specifically, these manifestations are the hallmark of that While lifespan is a measure that incorporates the impacts of aging, phase of life that follows the period of development and postnatal the determinants of longevity are distinct from those that influence growth, that follows a period of relative homeostasis during adult the rate at which an organism ages14. Furthermore, lifespan studies life associated with reproductive maturity, and that is character- are conducted in laboratory settings that allow for prolonged peri- ized primarily by a decline in structure and function. This third ods of protected aging15, just as human societies do, thereby mask- phase is the raison d’être for the field of geroscience5, and is also ing many increased risks of dying as a result of functional declines characterized in humans by a dramatic increase in the incidence with age that would be evident in the wild. Therefore, it is possible of age-related diseases, including cancer, cardiovascular diseases for measured lifespan to be uncoupled, at least to a large extent, and neurodegenerative diseases. Although the manifestations of from the consequences of aging—the recording of the death of a aging are a feature of later life, their underlying cellular and molec- person provides no information as to how functional that person ular bases certainly begin earlier and, arguably, at least for some was over the previous decades. While there is clearly an interre- molecular changes, even during development6. However, such lationship between aging and longevity, they are not inextricably molecular events can be identified as potential underpinnings of linked16. Evidence in Caenorhabditis elegans has provided support aging phenotypes only in retrospect, and all of these occur even in for this idea by demonstrating that genetic interventions that extend organisms with negligible senescence7. As such, no unified theory of lifespan may do so without comparably altering the relevant aging the molecular basis of cellular aging has emerged, primarily because phenotypes17. As such, it is imperative that quantitative measures of of the myriad of interacting contributions8, and we do not attempt aging itself—so called biomarkers—be increasingly used in order to to define aging, its potential causes or the time when the underly- understand the complex processes that underlie the manifestations ing changes begin (Box 2). We focus primarily on how the mani- of organismal aging. In addition, quantitative measures of aging will festations of aging, at the organismal level, reflect variants in the allow more rapid study of interventions to slow the rate of aging rate of tissue aging across space and time, and how they may arise of long-lived species, including humans, in which longevity studies 1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. 2The Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. 3Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. 4Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. ✉e-mail: [email protected]; [email protected] NatURE AGING | VOL 1 | JanuaRY 2021 | 29–35 | www.nature.com/nataging 29 PERSPECTIVE NATURE AGING Box 1 | Evolutionary theories of aging As the renowned geneticist and neo-Darwinian evolutionary the- switch later in life because the expression of these genes early in orist Teodosius Dobzhansky noted by the title of his 1973 essay, life has actually been selected for based on their benefcial efects. “Nothing in biology makes sense except in the light of evolution”84. Hence, the pleiotropy is the diferent traits in early and late life, Tis is particularly germane to the biology of aging since all mod- and the antagonism is the benefcial versus detrimental efects of ern evolutionary theories of aging begin by positing that aging those traits. Williams himself proposed a theoretical example: a traits are largely, if not entirely, outside of evolutionary selective mutation may favor calcifcation of bone during development but, pressure. Tis is based on the principle that the forces of natural in a diferent somatic environment (that is, the aged soma), leads selection diminish with age because of the myriad causes of ex- to calcifcation of the connective tissues of arteries. Te disposable trinsic mortality in the wild. Tus, the challenge has been to as- soma theory of Kirkwood4 takes a more physiological perspective cribe the features of aging to evolutionary processes that could, at to propose that an organism is able to shif allocation of its own least in theory, account for their existence. Early theories centered resources to either reproduction or to processes that maintain the around the idea that aging is genetically programmed and that soma (for example, growth, homeostasis, nutrient storage and so aging is somehow adaptive for the species. Tis notion has been on). In that sense, it is not a purely genetic theory, as those that increasingly discounted as evidence has failed to provide support came before were, and does not invoke genomic mutations or the and as subsequent theories have suggested plausible accounts for efects of specifc alleles to explain cell and tissue senescence. While aging phenotypes based on processes that are under the infuence previous theories certainly set aside the germline as a specifc case of natural selection and those that are not. separate from the soma in terms of aging, the disposable soma Te mutation accumulation theory, which is attributed to theory directly incorporates the germline as a critical component Medawar2, postulates that mutations accumulate in the germline of the equation about allocation of resources. Te theory rests on over generations, and that these mutations are largely, if not the notion of physiological trade-ofs in the context of broader entirely, insignifcant during development, growth and early genetic programs that support somatic maintenance and the adulthood (and are thus outside of evolutionary selection) but failure of those programs, which accounts for aging phenotypes. manifest themselves as deleterious in