Fight Aging!

The influential hallmarks of aging paper is now nearly ten years old. It has been twenty years since the Strategies for Engineered Negligible Senescence (SENS) categorization of causative mechanisms of aging was first put forward, an effort that inspired the hallmarks. Time moves on relentlessly! Are you feeling old yet? Unlike SENS, the hallmarks of aging made no attempt to be a to-do list of research and development approaches that we should be undertaking in order to effectively treat aging. They are, as it says on the label, hallmarks, observations of old cells and tissues. Nonetheless, a to-do list is somewhat the way in which the hallmarks have been taken in much of the research community, for better or worse. It is good that more of that community is on board with the treatment of aging as a goal to be achieved, but on the other hand some of the hallmarks are clearly far downstream from the root causes of aging, and thus probably poor targets for intervention.

Given the existence and popularity of the hallmarks of aging, far more cited and discussed than SENS ever was, what next? One might hope that today's open access paper illustrates something of the shape of what is next: that researchers talk less about the hallmarks of aging, and instead talk more about the approaches that might reverse aging, producing rejuvenation. The paper is something of a grab bag of presently popular strategies, with epigenetic reprogramming and senescent cell clearance leading the way. It offers only a partial coverage of the field, paying far too little attention to clearance of protein aggregates and lipofuscin, for example. Nonetheless, if more people thought this way, we might see faster progress towards the effective treatment of aging.

Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

For decades, one of the dominant theories in ageing research has been that ageing results from the accumulation of DNA changes, mainly genetic mutations, which prevent more and more genes from functioning properly over time. These malfunctions, in turn, can cause cells to lose their properties, leading to the breakdown of tissues and organs and ultimately to ageing and diseases. However, the emerging evidence claims that epigenetic information loss over time is the major cause of mammalian ageing, and epigenetic regulation can restore youthful gene expression patterns. For epigenetic rejuvenation, developing safe and stable strategies that modulate the epigenetic landscape of aged cells to a primitive state are important for cells to exert rejuvenating effects without cancer risk. Furthermore, systematic comparisons of epigenetic dynamics during ageing and partial reprogramming will contribute to identifying key checkpoints for reversing the ageing process and inform the design of potential intervention strategies for ageing-related diseases.

Pathological accumulation of senescent cells (SCs) is also associated with ageing and a range of diseases, and SCs may be potential pharmacological targets for delaying the ageing process. In respect of targeting SCs, there are still many potential markers, like chromatin dynamics and transcriptional signaling, and pharmacological interventions deserving exploitation, to effectively regulate the secretory phenotype of SCs. SC elimination and senescence-associated secretory phenotype inhibition have shown some efficacy in clinical studies of treating functional degeneration and chronic diseases in ageing.

Targeting the cell microenvironment and systemic signals makes sense for tissue-specific cell and organism rejuvenation. Stem cells play a crucial role in maintaining tissue homeostasis, and cell microenvironments also regulate stem cell behavior, which together form a regenerative unit. External signals from the ageing microenvironment appear to dominate the intrinsic function of young stem cells. In contrast, signals from the young microenvironment may have a limited effect on the regeneration of aged stem cells. It would be interesting to identify the genes or pathways that make aged stem cells insensitive to external signals in young microenvironment.

Although many clinical trials registered for stem cell treatments, an effective and safe stem cell therapy to slow or reverse tissue ageing has not yet been identified. Several obstacles still need to be overcome, including proper differentiation and integration of cells in tissues, maintenance of the youth of stem cells and their progeny in ageing tissues, and prevention of tumorigenesis. It will be important to determine the specific mechanisms, which have the potential to provide better treatment pathways - using stem cell transplantation or utilizing endogenous stem cell banks. Recent advances in single-cell transcriptomics and pedigree tracing techniques provide a systematic understanding of stem cell ageing mechanisms. The systematic identification of gene networks, involved in functional changes, age-dependent changes in RNA and protein and metabolite molecules, and cellular interactions, will contribute to further studies on stem cells in tissue repair and ageing-related diseases.

Despite the great progress in cellular rejuvenation, the potential limitations have led to cellular rejuvenation rarely being tested in human studies. Cellular rejuvenation for reversing ageing and age-related diseases as well as cancers has been extensively studied. While cellular rejuvenation holds great promise, key questions remain to be addressed.

(1) Cellular reprogramming strategy can reverse age-related physiological changes and promote tissue regeneration by resetting the epigenetic clock and changing cell fate, but the problems such as relatively low reprogramming efficiency and potential safety concerns, remain the obstacle in the path of its application.

(2) The pharmacological delivery system is difficult to express the pluripotency factors with high efficacy. The toxicity might be induced by drug combinations, then reducing the effectiveness of the cocktail and causing side effects in normal cells.

(3) Clearance of SCs and decreasing SASP exert a beneficial effect on organ repair and disease treatment, but poor cell selectivity of senolytics may result in the damage of normal tissue, and SASP inhibitors targeting specific secretory factors also have limited therapeutic effects on multiple factors-mediated diseases. Besides, completely senescence-specific markers are still absent.

(4) Stem cell therapy as a rejuvenative strategy holds great promise in the reversal of ageing and alleviation of diseases. Despite the advances in many clinical trials of stem cell therapy, optimizing in vitro culture environment, improving the delivery system of stem cells, and reducing immune rejection are still the major challenges to obtain high-quality stem cells and enhance that therapeutic effect.

(5) Restoring defective intercellular communications by the inhibition of inflammation can rejuvenate ageing-impaired changes, but long-term inflammation inhibition may lead to immunosuppression.

Collectively, cellular rejuvenation holds great promise for preventing and treating ageing-related diseases from different dimensions. A healthy and rejuvenated state of the organism can maintain stable characteristics and biological functions without excessive ageing-related degeneration or deterioration. The development of various cellular rejuvenation strategies provides compelling evidences that the ageing process is not irreversible. Particularly, the effectiveness of stem cell therapy and dietary restriction has been tested in the real world, yielding to desired results. Hopefully, there is a great possibility of translation of these rejuvenation strategies to address human ageing, age-associated diseases, and cancers. Therefore, it is reasonable to expect that clinical rejuvenation approaches to treat ageing-related diseases and even to reverse ageing will be boomed within the next two or three decades.