A Review of Presently Popular Approaches for the Construction of Therapies to Slow or Reverse Aging

This open access review paper surveys the present major areas of interest in the development of therapies expected to slow or reverse aging to some degree. Of the well-funded and popular lines of research and development, only one is unequivocally a form of rejuvenation, the new field of senolytic therapies able to selectively destroy senescent cells. Of the others noted, only stem cell therapies and possibly upregulation of neurogenesis have the potential to become rejuvenation therapies, at the point at which researchers become able to reliably replace damaged cell populations with fresh, functional cell populations. That point has not yet been reached.

The rest of the items, which account for the majority of present research efforts in the treatment of aging, are either (a) the well known lifestyle factors such as exercise and calorie restriction, or (b) attempts to override undesirable cell behavior without actually fixing the damage and dysfunction that underlies that altered behavior in aging. The scope of potential benefits is thus limited; trying to keep a damaged machine running by tinkering with the controls is a challenging way to eke out only incremental gains. The future that must come to pass, if we are to see significant extension of human life span in the decades ahead, is one in which the fields of rejuvenation research not listed in this paper, the other portions of the SENS damage repair agenda beyond senolytics, must become as large and well-funded and popular as senolytics is today.

Finding ways to prevent age-related diseases is important because the aging population is snowballing in the world as a result of better nutrition, effective antibiotics against infectious diseases, and improved healthcare. Development of interventions that slow down the rate of aging and reduce or postpone the incidence of debilitating age-related diseases would be of immense value to improve the quality of life as well as to reduce medical costs. Studies in animal models have demonstrated that a variety of genetic, dietary, and pharmacological interventions enhance lifespan. Some of the anti-aging strategies that extend lifespan may also be useful for delaying the onset of age-related diseases.

Autophagy has a significant role in the modulation of the aging process. The function of autophagy in aging is apparent from numerous studies using yeasts, worms, flies, and mice that elevated expression of autophagy-related genes is a prerequisite for lifespan extension. Some studies have also shown that tissue-specific expression of single autophagy gene is adequate for extending lifespan whereas other studies have pointed out that distinct types of autophagy are critical for longevity as they specifically target dysfunctional cellular components and prevent their aberrant accumulation. Interestingly, slow-down of aging and longevity increase achieved through food deprivation and calorie restriction (CR) are facilitated through upregulation of autophagy. Thus, autophagy enhancing interventions that commence in middle age would likely facilitate successful aging and increased longevity.

Amongst the perpetrators of organismal aging, the function of senescent cells (SCs) has caught significant interest. Senescent cells disrupt the milieu by producing a plethora of bioactive factors that cause inflammation and impede regeneration. Senescent cells actively propel spontaneously ensuing age-related tissue deterioration and thereby promote several diseases associated with aging. In several tissues and organs, senescence is a common feature during the aging process with an age-related increase in the number of senescent cells. From the above, it appears that, the elimination of senescent cells using drugs referred to as senolytics would slow down aging and maintain better function during old age. In mice, senotherapy proved to be effective in models of accelerated aging and also during normal chronological aging. Senotherapy prolonged lifespan, rejuvenated the function of bone marrow, muscle and skin progenitor cells, improved vasomotor function and slowed down atherosclerosis progression.

A new procedure for limiting or reversing aspects of aging in various organs throughout the body is the transfusion of blood from the young to the aged, as molecules circulating in the young blood can rejuvenate the aging cells and tissues. Studies suggested that several soluble factors underlie the rejuvenating effects of the young blood. The growth differentiation factor 11 (GDF11) is one of the well-characterized factors in the young blood. Clinical trials testing the effect of young plasma in patients with Alzheimer's disease are already underway, but careful, placebo-controlled larger clinical trials will be required.

Recently, many studies have shown that intermittent fasting (IF) can have similar effects as CR. Benefits related to cardiovascular health include protection of heart against ischemic injury, reduced body mass index and blood lipids, improved glucose tolerance, and lower incidence of coronary artery disease. The positive effects of IF on brain health in pre-clinical studies comprised improved cognitive function with reduced oxidative stress during middle age when IF was commenced in young adult age and delayed occurrence of age-related brain impairments. In human studies, protocols and interpretations of IF-mediated weight loss trend varied considerably. Most human IF studies did not result in significant weight loss or considerable improvements in metabolic biomarkers. Quite a few questions remain to be dealt with regarding the benefits of IF on human health.

Studies in animal models have shown that hippocampal neurogenesis decreases during aging, and the overall decrease is exacerbated in Alzheimer's disease. The precise mechanistic causes underlying age-related decline in neurogenesis are unclear. Overall, it appears that age-related reductions in stem cell mitogenic factors, microvasculature and cerebral blood flow, and low-grade inflammation influence reduced neurogenesis in aging because increased neurogenesis could be obtained through interventional strategies that upregulate the concentration of neural stem cell (NSC) mitogenic factors or improve the microvasculature density and diminish inflammation. Pharmacological mimetics of exercise capable of enhancing both hippocampal neurogenesis and BDNF appear to be useful for improving cognitive function, and thus combined neurogenesis and BDNF boost during adulthood and middle age may postpone cognitive aging and onset of Alzheimer's disease.

The benefits of regular physical exercise (PE) for conserving the function of the cardiovascular, musculoskeletal and nervous systems are well known. Regular PE commencing from young or middle age appears to be a necessary lifestyle change for maintaining good health in old age. Since drugs that significantly prevent age-related cognitive decline are yet to be discovered, it is vital to start PE regimen early in life when the neural reserve is still adequate, to completely avoid or at least postpone the cognitive decline. However, the amount of PE required in young or middle age to maintain healthy cognitive function in old age is yet to be ascertained.

The efficacy of intracerebral transplantation or peripheral injection of a variety of stem cells including mesenchymal stem cells (MSCs), NSCs or glial-restricted progenitors (GRPs) has been examined in animal models to improve the function of the aging brain. Stem cell therapy has been shown to mediate beneficial effects in several age-related neurodegenerative disease models. Studies revealed that the mechanism underlying a better cognitive function involved improved hippocampal synaptic density mediated by BDNF. In addition to stem cell grafting approach, activation of endogenous cells in some regions of the body has promise for mediating regeneration during aging.

In conclusion, there are many anti-aging strategies in development, some of which have shown considerable promise for slowing down aging or delaying the onset of age-related diseases. From multiple pre-clinical studies, it appears that upregulation of autophagy through autophagy enhancers, elimination of senescent cells using senolytics, transfusion of plasma from young blood, neurogenesis and BDNF enhancement through specific drugs are promising approaches to sustain normal health during aging and also to postpone age-related diseases. However, these approaches will require critical assessment in clinical trials to determine their long-term efficacy and lack of adverse effects on the function of various tissues and organs.

Link: https://doi.org/10.14336/AD.2018.1026

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