Molecular and cellular pathways of aging in hematopoiesis

Aging is defined as the time-related downgrade of the functions of an organism necessary for survival and fertility. Both genetic and environmental factors influence aging, which involves several cellular and molecular changes occurring in cells, tissues, and the whole organism. In vertebrates, the process of aging begins at conception and extends to the continuum of all life stages, up to the geriatric one.

Increased life expectancy is one of humanity's greatest achievements. The elderly population has increased in the last few decades due to scientific and technological advancements that have improved living conditions and have led to efficient therapeutic management of age-related disorders. By 2050, the population over 60 years of age is expected to double worldwide [[1]]. Despite the scientific accomplishments in aging research, globally many elderly people still find themselves in unsupportive environments. To address this need, various initiatives have been implemented to help the rapidly growing number of aged persons to be healthy and contribute to their families and societies. The Healthy Ageing Collaborative of the World Health Organization aims to improve the lives of the elderly, support the implementation of the United Nations Decade of Healthy Ageing (2021–2030) and other related initiatives, strengthen international collaboration on healthy aging, and recognize the role of older individuals. The Decade of Healthy Ageing focuses on developing age-friendly environments and improving healthcare systems. Under these initiatives, aging-related research is a priority [[2]], and various challenges linked to the molecular understanding, prognosis, diagnosis, and therapeutic management of age-related disorders, including the hematological ones [[3-5]], need to be addressed. In line with this direction, this Special Issue focuses on aging-related research in hematopoiesis.

Basic research in the last few decades has contributed to our understanding of the molecular mechanisms of aging. Various interconnected hallmarks of aging have been defined, including genomic instability, telomere attrition, cellular senescence, stem cell exhaustion, chronic inflammation, dysbiosis, and alterations/deregulation in the epigenome, proteostasis, macroautophagy, nutrient-sensing, mitochondrial function, and intercellular communication [[6]]. These hallmarks are also observed in cells of the hematopoietic system including hematopoietic stem cells (HSCs), offering multiple opportunities to reverse aging by therapeutically modifying the associated cellular processes and pathways.

As humans age, multiple changes occur in the bone marrow, leading to hematological disorders, including cytopenias, defects in immune responses, and hematologic malignancies [[7]]. HSCs ensure a balanced production of all blood cell lineages throughout life. Upon aging, HSCs gradually lose their self-renewal and regenerative capacity, and a global decline in their functions takes place, due to internal and external stimuli. External (e.g., niche interactions) and cell-intrinsic stress (e.g., metabolic and replicative stress), contribute to DNA damage and increased frequency of genomic mutations [[8]]. However, the majority of the causes underlying HSC aging are considered to result from cell-intrinsic pathways [[9]]. When comparing young and old animal models and humans, overall cell numbers, senescence, differentiation in lineages, cellular composition, and HSC functions differ significantly. Hematologic malignancies are linked to increased mortality rates in the elderly population and account for serious clinical and scientific challenges that remain to be decoded. Leukemia is a progressive malignant disease defined by the overproduction of abnormal hematopoietic cells, more prevalent in older patients, with a median diagnosis of 67 years of age.

A complete delineation of the molecular and cellular pathways and mechanisms underlying the aging of HSCs is important, as the findings will be translated into developing novel strategies for their rejuvenation. As various aspects of the aging process are reversible [[9]], prevention of age-associated disorders and hematological malignancies can be accomplished. Therefore, improved therapeutic management approaches for age-related hematopoietic defects constitute an important priority today, and strategies to modify and rejuvenate HSCs are a clinical necessity. Despite important research achievements in the field, further efforts are required to fully elucidate the underlying molecular mechanisms of HSC aging.

The Special Issue ‘Molecular and cellular pathways of aging in hematopoiesis’ presents a unique collection of seven state-of-the-art Review articles authored by leading scientists working on the molecular mechanisms, pathways, and key factors involved in HSC aging and aging-related pathologies (mainly leukemias). The involvement of epigenetics and inflammation in connecting the aging of HSCs, clonality, and leukemogenesis [[10]], and the challenges in clarifying the aging mechanisms and developing therapeutic interventions to rejuvenate HSCs are also discussed. The first four articles of the Special Issue focus on HSC functions, transcriptomic signatures, RNA modifications, and rejuvenation, and the last three on specific factors (CBXs, DUBs, STATs) and their role in normal hematopoiesis and leukemia (Fig. 1).

In conclusion, this Special Issue provides insights into various key molecular/cellular pathways of aging in hematopoiesis linked to the age-related functional decline of HSCs and the subsequent development of hematopoietic age-related disorders. Such disorders impair the quality of life of the elderly and increase the economic costs of their therapeutic management. Further basic, translational, and clinical research on aging in hematopoiesis is expected to address such social needs. A complete understanding of the mechanisms of HSC functional decline during aging will provide novel means to decelerate the process of aging. Successful rejuvenation strategies of HSCs, already tested in model organisms, can be applied to humans. The heterogeneity in aging mechanisms between individuals, which in the past has constituted a barrier to the successful correction of age-related hematopoietic changes, can be addressed today by the application of single-cell omics technologies. This Special Issue, together with many other relevant published studies, and technological advances contributing to the study of hematopoiesis at the multi and single-cell level, set a solid base for further research towards a complete understanding of the mechanisms of aging in hematopoiesis. Therapeutic management of age-related disorders in a personalized way is expected to be possible shortly.