Paradigms in Antiaging Medicine: Prejuvenation, Rejuvenation and Age Reversal

Paradigms in Antiaging Medicine: Prejuvenation, Rejuvenation and Age Reversal 

Dr. Thet Lwin

MBBS, MSc (Cardiology and Stroke) UK

Medical Consultant/ Academic Clinical Fellow, European Wellness Villa Media, Germany and Thailand

Medical Director, Soul Clinic, Myanmar

Medical Advisor, IV LYFE Wellness, Thailand

Abstracts

Aging, a progressive loss of physiological integrity leads to impaired function and increased vulnerability to death. In updated aging science, there are a lot of major contributing factors in aging process and many cellular, intercellular and intracellular disarray of important mechanisms and processes have been researched very well.

In this article, these contributing hallmarks and related conditions will be explained and updated interventions for the process of reversing age-related degeneration will be briefly described. 

Aging is a progressive loss of physiological integrity leads to impaired function and increased vulnerability to death 

Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.

Introduction

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 pathophysiology of morbid degenerative conditions and chronic diseases including cancer, diabetes, cardiovascular disorders, metabolic disorders and neurodegenerative diseases.

In updated aging science, there are a lot of major contributing factors in aging process and many cellular, intercellular and intracellular disarray of important mechanisms and processes have been researched very well but more detail and large-scale research are still needed in spite of good progress and potential not only in reversing and rejuvenating aging but also in prejuvenation by protective and futuristic interventions.

Major contributing factors in age related degeneration will be explained under respective sections and a brief explanation for evidence-based interventions for reversing those problems will be related.

DNA related damage (DNA damage, Epigenetic alterations and Telomere attrition) and defective protein homeostasis (Proteostasis and Autophagy)

In considering major hallmarks of aging, there are some primary reasons that have negative deterioration such as DNA damage, mitochondrial DNA mutations, epigenetic drift, telomere loss and defective proteostasis.

There is an extensive evidence that genomic damage accompanies aging and can causes many consequences.

All cells and tissues are affected by various epigenetic alterations throughout life (Talens et al., 2012). Epigenetic changes involve alterations in DNA methylation patterns, posttranslational modification of histones, and chromatin remodeling. Apart from accumulation of DNA damage, some chromosomal regions are susceptible to age-related deterioration and normal aging is accompanied by telomere attrition in mammals. (Blackburn et al., 2006)

Not just in maintaining DNA functions, cells have to preserve the stability and functionality of their proteomes. Aging and some aging-related diseases are linked to impaired proteostasis. In proteostatic mechanism, escalating malfunction in the regulatory processes of maintenance, repair, and turnover of defective protein structures and organelles is likely to represent a primary cause of the cellular disorganization associated with aging.

Autophagy is an evolutionary conserved cellular housekeeping pathway responsible for the degradation of misfolded proteins and exhausted organelles and has been increasingly demonstrated to play a major role in maintaining cellular homeostasis and influencing lifespan and longevity (Filfan et al., 2017; Madeo et al., 2015; Madeo et al., 2010).

Mitochondrial dysfunction, Cellular senescence and defective nutrient sensing mechanisms

In contrast to above major hallmarks, there are also some important ones that have beneficial effects at low levels but become deleterious at high levels. Those involve dysfunctional mitochondria, ROS cell signaling pathway, senescence and some nutrient sensing mechanisms. These hallmarks can be regarded as protectors of organism from damage or from nutrient scarcity. But when they are exacerbated or chronic, they generate further damage.  (Carlos Lo’pez-Oti’n et al., 2013).

Dysfunctional mitochondria can contribute to aging independently of ROS (Edgar et al., 2009; Hiona et al., 2010). The principle of cellular senescence was originally described by Hayflick in human fibroblasts serially passaged in culture (Hayflick and Moorhead, 1961). Cellular senescence can be defined as a stable arrest of the cell cycle coupled to stereotyped phenotypic changes (Campisi et al., 2007; Collado et al., 2007).

Deregulated Nutrient Sensing

When we consider the true holistic rejuvenation and regeneration of aging related consequences, apart from cellular senescence and cellular component dysfunction like mitochondrial damage, the ability of the cells in nutrient sensing mechanism is also an essential component of factors contributing to age related degeneration of cellular mechanism.

Some important cellular nutrient sensing pathways have been explained in brief in the section of loss of proteostasis and autophagy mechanism and more connections and link to aging related problems will be explained more in this section.

Among cellular nutrient sensing pathways, Insulin and IGF-1 signaling pathway (IIS pathway) is one of major pathways and other interconnected nutrientsensing systems are: mTOR, for the sensing of high amino acid concentrations; AMPK for low-energy states by detecting high AMP levels; and sirtuins for low-energy states by detecting high NAD+ levels (Houtkooper et al., 2010) (Martin et al., 2015)

Cellular Function Decline, Intercellular Communication Problems, Inflammation and Immunosenescence

Major contributing factors in degenerative mechanisms of aging have well been explored in brief. In performing full and effective tissue and organ function, every individual cell is important in its own functioning power. Furthermore, cell to cell communication is also an important aspect in full and effective functioning of the tissues and organs.

Among characteristics of aging, the decline in the potential of regeneration of tissues is one of the most obvious ones and that stem cell exhaustion can cause consequences of age-related damages and disorders. Therefore, stem cell rejuvenation may reverse the aging (Rando and Chang, 2012).

Salminen et al., had stated a prominent aging-associated alteration in intercellular communication, a proinflammatory phenotype that accompanies in aging in mammals called ‘‘inflammaging”. (Salminen et al., 2012).

These alterations result in an enhanced activation of the NLRP3 inflammasome and other proinflammatory pathways, finally leading to increased production of IL-1b, tumor necrosis factor, and interferons (Green et al., 2011; Salminen et al., 2012).

Furthermore, the function of the adaptive immune system declines (Deeks, 2011). This immunosenescence may play a role in aggravation of systemic level aging phenotype and may cause the failure of the immune system to clear infectious agents, infected cells, and cells on the verge of malignant transformation.

Interventions for age reversal and rejuvenation

From antiaging standpoint and for true regeneration of aging and degeneration, biologics from blood products and various kinds of cell therapy products and ATMPs (Advanced Therapy Medicinal Products) are amazing paradigms in regenerative medicine.

But all these regenerative products will be cleared from the body after some time depending upon the nature, quality and type of products and depending upon the recipients’ clinical conditions. Therefore, to get the best benefit of regenerative products, first, it is important to correct problems that can worsen the aging related hallmarks that are explained in previous sections.

In proper functioning of vital organs, tissues have to rely on functional cells for viability of organs. When functional cells die off, new cells from our stem cell pool usually replace.

Furthermore, metabolic homeostasis become dysfunctional and hallmarks of metabolic dysfunction include dysregulation of AMPK, FOX0 and SIRT1, depletion of NAD+, and excessive of mTOR. (Laplante M et al., 2012) (Khorraminejad-Shirazi M et al, 2017)

Apart from those paradigms in age reversal interventions, the role of caloric restriction is also important as explained in autophagy section.

Moreover, other effective weapons such as metformin and nutraceuticals such as curcumin, green tea and hesperidin are also in interesting evidences.

Immunosenescence and Reversal of immune Aging

In scientific research, many biomedical approaches targeting age related degeneration have been done a lot in animal models and some of them was able to reverse aging in adult mammals based on various physiological measurements. (Daset al., 2018; Ocampo et al., 2016; Zhang et al., 2017).

Recently, the first human clinical trial designed to reverse aspects of human aging, the TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial, done in 2015–2017 has released the trial result. (Fahy GM et al., 2019) The results support the goal and show the evidence that regression of multiple aspects and biomarkers of aging is possible in man.

Conclusion

Aging science and research to target age related degenerated consequences and immune problems have been in rapid development. But better understanding of mechanisms behind age related problems and detail intervention with large scale research are still needed.

Until now, various advanced finding and clinical correlations have been established and many more advancements are on the way for true rejuvenation and regeneration. Furthermore, preventative approach and futuristic interventions for prejuvenation are alarming.

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Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.