Hallmarks of Health López-Otín, Carlos; Kroemer, Guido
Cell,
01/2021, Letnik:
184, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or ...hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration). Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system coupled to the loss of numerous stigmata of health.
Rather than an absence of disease, health can be defined by its active features: spatial compartmentalization, maintenance of homeostasis, and appropriate responses to stress.
Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the ...opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
Aging is a complex and multifactorial process. This reprise of the 2013 “The hallmarks of aging” reviews conceptual progress, additional hallmarks of aging, their interconnection, and preclinical anti-aging manipulations.
Frailty has long been an important concept in the practice of geriatric medicine and in gerontological research, but integration and implementation of frailty concepts into clinical practice in the ...United States has been slow. The National Institute on Aging (NIA) Intramural Research Program and the Johns Hopkins Older Americans Independence Center sponsored a symposium to identify potential barriers that impede the movement of frailty into clinical practice and to highlight opportunities to facilitate the further integration of frailty into clinical practice. Primary and subspecialty care providers, and investigators working to integrate and translate new biological aging knowledge into more specific preventive and treatment strategies for frailty provided the meeting content. Recommendations included a call for more specific language that clarifies conceptual differences between frailty definitions and measurement tools; the development of randomized controlled trials to test whether specific intervention strategies for a variety of conditions differently affect frail and non‐frail individuals; development of implementation studies and therapeutic trials aimed at tailoring care as a function of pragmatic frailty markers; the use of deep learning and dynamic systems approaches to improve the translatability of findings from epidemiological studies; and the incorporation of advances in aging biology, especially focused on mitochondria, stem cells, and senescent cells, toward the further development of biologically targeted intervention and prevention strategies that can be used to treat or prevent frailty. J Am Geriatr Soc 67:1559–1564, 2019
Proteases are a set of enzymes that have been involved in multiple biological processes throughout evolution. Among them, extracellular matrix (ECM) remodeling has emerged as one of the most relevant ...functions exerted by these proteins, being essential in the regulation of critical events such as embryonic development or tissue homeostasis. Hence, it is not surprising that dysregulation in any protease function that affects ECM homeostasis may contribute to the aging process. Matrix metalloproteinases (MMPs) are one of the most important families of proteases involved in the tight control of ECM remodeling over time. In this review, we will discuss how MMPs and other proteases alter ECM composition and mechanical properties in aging, thereby affecting stem cell niches and the development of senescent phenotypes. Finally, we will summarize recent findings that associate MMPs with the development of age-related diseases, such as neurodegenerative disorders.
•The ECM undergoes multiple remodeling events mediated by MMPs during aging.•ECM composition and mechanical properties are affected by aging-associated remodeling.•Aged ECM influences stem cell behavior and development of senescent phenotypes.•Age-related decline in MMP activity is associated with the progress of neurological diseases.
The Hallmarks of Aging López-Otín, Carlos; Blasco, Maria A.; Partridge, Linda ...
Cell,
06/2013, Letnik:
153, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major ...human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.
The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as ...the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
Kinases and proteases are responsible for two fundamental regulatory mechanisms--phosphorylation and proteolysis--that orchestrate the rhythms of life and death in all organisms. Recent studies have ...highlighted the elaborate interplay between both post-translational regulatory systems. Many intracellular or pericellular proteases are regulated by phosphorylation, whereas multiple kinases are activated or inactivated by proteolytic cleavage. The functional consequences of this regulatory crosstalk are especially relevant in the different stages of cancer progression. What are the clinical implications derived from the fertile dialogue between kinases and proteases in cancer?
The connectivity of mitochondria is regulated by a balance between fusion and division. Many human diseases are associated with excessive mitochondrial connectivity due to impaired Drp1, a ...dynamin‐related GTPase that mediates division. Here, we report a mitochondrial stress response, named mitochondrial safeguard, that adjusts the balance of fusion and division in response to increased mitochondrial connectivity. In cells lacking Drp1, mitochondria undergo hyperfusion. However, hyperfusion does not completely connect mitochondria because Opa1 and mitofusin 1, two other dynamin‐related GTPases that mediate fusion, become proteolytically inactivated. Pharmacological and genetic experiments show that the activity of Oma1, a metalloprotease that cleaves Opa1, is regulated by short pulses of the membrane depolarization without affecting the overall membrane potential in Drp1‐knockout cells. Re‐activation of Opa1 and Mitofusin 1 in Drp1‐knockout cells further connects mitochondria beyond hyperfusion, termed extreme fusion, leading to bioenergetic deficits. These findings reveal an unforeseen safeguard mechanism that prevents extreme fusion of mitochondria, thereby maintaining mitochondrial function when the balance is shifted to excessive connectivity.
SYNOPSIS
The balance between membrane fusion and fission controls mitochondrial connectivity and function. Here, short pulses of membrane depolarization are found to drive an Oma1‐dependent stress response termed ‘mitochondrial safeguard’ that protects mitochondrial function upon increased mitochondrial connectivity.
A mitochondrial stress response adjusts the balance between fusion and fission in response to increased mitochondrial connectivity in mammalian cells.
Loss of mitochondrial GTPase Drp1 induces flickering, a repeated and transient decrease of mitochondrial membrane potential.
Flickering partially activates the metalloprotease Oma1 and proteolytically inactivates Opa1 GTPase in Drp1‐knockout cells.
Unless inactivated, Opa1 along with Mfn1 causes extreme mitochondrial fusion in Drp1‐knockuot cells.
Extreme fusion of mitochondria leads to bioenergetic deficits.
Short pulses of membrane depolarization drive a mitochondrial stress response, named mitochondrial safeguard, that maintains mitochondrial function in response to excessive organelle connectivity.
Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or ...mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.
Meta-hallmarks of aging and cancer López-Otín, Carlos; Pietrocola, Federico; Roiz-Valle, David ...
Cell metabolism,
01/2023, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Both aging and cancer are characterized by a series of partially overlapping “hallmarks” that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic ...alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common “meta-hallmarks,” while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly “antagonistic hallmarks.” Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
Cancer is an age-associated disease. López-Otín et al. discuss which hallmarks of aging coincide with the hallmarks of cancer and hence constitute meta-hallmarks explaining the time-dependent manifestation of malignancy. The authors also examine specific characteristics of the aging process that antagonize oncogenesis.
PDF
