Hallmarks of Aging: Causes and Consequences

Over the past decade, there has been notable advancement in the field of aging, with numerous preclinical and clinical investigations focusing on aging and age-related diseases. A recent review article published in the journal Cell by López-Otín and colleagues has presented an updated perspective on the hallmarks of aging. These authors conducted an extensive literature review and outlined 12 hallmarks of aging, which are categorized into three groups: primary, antagonistic, and integrative. This updated model of aging comprehensively encompasses the fundamental characteristics of the aging process and includes novel pathways that play a pivotal role in age-related processes, such as dysbiosis, chronic inflammation, and impaired macroautophagy. The authors have also made substantial efforts to interconnect the updated hallmarks of aging with each other, as well as with the recently proposed hallmarks of health. They have provided several illustrative examples of mechanistic interpretations of the model. Undoubtedly, this comprehensive overview of the hallmarks of aging will serve as a valuable reference and a starting point for future investigations.

While the updated hallmarks of aging offer a valuable framework for characterizing the aging phenotype, it is essential to recognize that aging results from a mechanistically intricate and interrelated series of changes that occur continuously throughout an organism's lifespan. When the initial nine hallmarks of aging were introduced in 2013, our understanding of the mechanisms of aging was limited. Since then, numerous research groups have elucidated various mechanisms underlying this process, introducing the concept of the sequential nature of changes over time and the molecular basis of aging. Therefore, it is suggested that the hallmarks of aging can benefit from incorporating information about the temporal and sequential aspects of the aging process. This commentary aims to delve into the key mechanisms underpinning aging phenotypes and their connections to each hallmark of aging and to each other. In doing so, it proposes a shift from systematically describing and categorizing the hallmarks of aging towards a model of aging that strives to dissect the timing and causes of affected phenotypes.

The aging process is commonly divided into early and late events, with a clear distinction between aging phenotypes and the underlying molecular events. Aging encompasses molecular, physiological, and phenotypic changes that vary in clinical significance and short-term or long-term outcomes if targeted using pharmacological interventions. Therefore, a "three-wheeled gears" model (Figure 1) is proposed to depict the early (upstream), intermediate, and late (downstream) events of aging, which roughly correspond to the primary, antagonistic, and integrative hallmarks of aging as proposed by López-Otín and colleagues. All the gears in this model are interconnected, and the movement of one wheel, representing progress or accumulation, induces movement in all the other wheels. In this model, it is suggested that cellular stress could be one of the initial triggers of the aging process, recognizing that the nature of the stressor may differ for each cell, tissue, and organ.

Environmental cues (e.g., pollution, infection, heat, and cold) induce cellular stress and disrupt fundamental molecular processes, leading to epigenetic changes, transcriptional noise, release of chromatin to the cytoplasm, DNA damage in the nucleus and mitochondria, loss of translational fidelity, oxidative stress, and disruption of the cell membrane. The latter process, although a long-standing theory and supported by an increasing body of data, has been relatively less explored compared to other processes in this group. The type of cellular stress influences which molecular processes are primarily affected in the cell, but several processes can be affected by the same stressor. The early events of aging are highly interconnected and often trigger multiple responses. Detecting these early molecular events can be challenging without specialized technologies and tests, which are rarely available in clinical settings. Molecular alterations and disruptions in cellular processes due to cellular stress create "inflection points" that need to be resolved to restore the cell to a healthy state. If not resolved, molecular changes resulting from repeated stress throughout an organism's life accumulate over time and eventually become noticeable in aged individuals as "hallmarks" of aging. As these early events occur in the initial stages of the aging process, they present attractive targets for developing interventions to slow the upstream processes of aging and delay the onset of age-related diseases.

Intermediate events of aging encompass cellular responses to stress-induced molecular alterations and involve adjustments in cellular processes to adapt to the evolving molecular makeup of the cell. These physiological reactions aim to maintain cellular homeostasis and assist cells in re-establishing a healthy equilibrium. Intermediate events of aging include inflammation, proteostasis, autophagy, energy homeostasis, senescence, and the rewiring of cellular metabolism, including the sensing and turnover of lipids, sugars, and proteins. Although these are natural cellular processes, their prolonged deregulation alters the cell's status and can eventually manifest as antagonistic hallmarks of aging. Intermediate events of aging are promising targets for therapeutic interventions, as intervening in these pathways can help prevent the progression of cellular changes and slow the deterioration of cellular health.

Late events of aging involve the phenotypic manifestation of changes that have occurred at the molecular and physiological levels and are closely related to the integrative hallmarks of aging described by López-Otín and colleagues. Although aging phenotypes may vary depending on the tissue, they all lead to the progressive deterioration of organ function. Late events of aging encompass stem cell exhaustion, dysfunction in the immune system, including chronic inflammation, organ dysfunction, loss of tissue integrity, and alterations in tissue-tissue interactions and cell-cell communication, including dysbiosis. These processes are interconnected and can mutually influence each other.

Currently, therapeutic approaches aimed at aging phenotypes primarily focus on ameliorating aging symptoms rather than targeting the underlying molecular and cellular mechanisms. However, recognizing the aging phenotype is essential for deciphering the mechanisms underpinning aging and age-related diseases. The proposed model of aging is influenced by a recent review by Campello and colleagues, which discussed the molecular and metabolic mechanisms of retinal aging. It is also inspired by peer discussions concerning the mechanisms of aging, the molecular and physiological changes that occur during an organism's lifespan, and the phenotypic changes recognized as "aging" by experts and non-experts alike. This model is not final but should serve as a reference for new ideas and as a starting point for a more profound understanding of aging at the cellular and molecular levels. It is hoped that this model will aid researchers studying aging in designing future mechanistic studies and developing reliable animal models of aging, which are currently limited.

Complex biological processes such as aging cannot be fully understood without addressing the molecular and cellular mechanisms contributing to the different characteristics of aging and without dissecting the temporal and causal sequence of events. To provide a more holistic perspective on aging, an integrative model for the hallmarks of aging has been presented, offering a novel approach to presenting the current knowledge of aging-related processes. Despite recent progress in the field, there is still much to learn about the mechanisms of aging. Rather than establishing a status quo, the proposed model aims to stimulate discussion within the aging research community, guide future efforts in the field, and provide new avenues for investigation. This "three-wheeled gears" model can also assist in identifying new measures of aging and establishing new endpoints for clinical trials aimed at reversing or slowing aging. As argued here, a better understanding of the mechanisms of aging is crucial for the development of effective interventions that target molecular pathways and early cellular events that drive aging, rather than solely addressing one or more aging phenotypes.