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Aging As A Biological Target

2 months, 1 week ago

2245  0
Posted on Oct 01, 2018, 2 a.m.

The oncoming silver tsunami and chronic health problems related to the aging populations threaten to disrupt economies and degrade quality of life in the later years in the developed world.

Fundamental aging processes can be targeted via genetic, nutritional, and pharmacologic interventions that have been shown by studies not only to enhance but also extend health as well as longevity in animal models, with findings that clearly demonstrate biological rates of aging can be slowed.

There is abundant evidence in animal models of the geroscience hypothesis linking these biological discoveries to human health by proposing targeting biological aging processes can prevent or a minimum delay of onset and progression of numerous chronic diseases and debilities typically observed in older populations. Interventions extending mice lifespans often prevent and/or slow progress of several types of cancers, improve heart function, reduce atherosclerotic lesions, improve vaccine response, and alleviate normal age related cognitive loss.

Every year the US government publishes the rate of death from individual diseases stratified by age; the rate of death increases logarithmically with advancing age for virtually all major causes of death, and the incidence of multimorbidity also increases exponentially with age, Increasing numbers of individuals are being treated for 3 or more different diseases with at least 3 different treatments, each of which with potential adverse side effects and drug interactions. Prevention of individual diseases will have limited effect on health if one disease is replaced with another. Biological aging processes are the fundamental cause of most major medical conditions and disease, targeting these processes should hold great promise to ameliorate many of these issues as a group.

A number of aging pillars, interacting molecular and physiological processes underlying the biology of aging such as metabolism, proteostasis, inflammation, epigenetics, stress, macromolecular damage, stem cells and their aging have been revealed by geroscience studies. Important feature to this work is these processes are understood to be interrelated, findings have emerged from progress made via dissecting aging process in model organisms.

Opportunities for intervention have been provided by studies showing discovery of molecular and cellular pathways modulating healthy aging in diverse species across evolutionary distances. Genetic and dietary interventions have extended health and longevity such as knocking out rps6kb1 genes extending life of healthy female mice, overexpression of Sirt6 extends the life of male mice, and reducing caloric intake or methionine levels extends lives of both.

Drugs have also helped to extend health and longevity. ITP evaluates drugs to determine whether they prevent disease and extend life in genetically heterogeneous mice via studies that are conducted independently at 3 centers to control for lab specific environmental differences and provide immediate experimental confirmation. 26 candidate drugs have been evaluated to date with 6 being shown to extend life in at least one mouse gender. Combination of metformin and rapamycin have produced the largest overall increase in longevity which indicates that a combination therapy may be applied for synergistic effects. Studies suggest that interventions could significantly extend life by more than 20 years and increase health spans even more substantially.

Simultaneous modulation of several aging pillars is possible, improvement of one often has positive effect on others. Most genetic and chemical interventions shown to extend life spans exert activating effects on autophagy that has also been shown malfunction in many age related diseases.

Age related disorders have been shown to be associated with cellular senescence. With aging processes senescent cells are not cleared away by the immune system efficiently, persistent presence causes inflammation states that contribute to tissue dysfunction. Presence of senescent cells are also associated with many pathologic conditions, senolytic interventions targeting those cells have been shown to improve health and extend life in animal models.

In theory maximum human life expectancy is around 115 years. At present average life expectancy within the USA is 80 years old, these remaining 35 years have yet to be realized. Centenarians live longer than most people and have an extra 20-30 years of health to go along with a shorter period of morbidity at the end of life. Some underlying mechanisms for these extra years have been discovered, but to achieve extend health of centenarians drugs may likely be needed. Acarbose has been shown to prevent diabetes, hypertension, and cardiovascular events. Rapamycin improves vaccine responses. Metformin has been shown to reduce risk of type 2 diabetes, cardiovascular disease, and cognitive decline, with similar reductions shown in observational studies for cancer, dementia, and total mortality; and an excellent safety profile across more than 60 years of use.

Geroscience has resulted in exciting and important studies in animal models, yet significance has only trickled slowly to the waters of the medical community. A major challenge for improving health via targeting human aging processes is from a regulatory perspective as there is no indication that is similar to targeting aging. Even when a safe and effective drug is available health care payers are reluctant to pay for treatment without regulatory approval, in turn making most drug companies reluctant to invest in treatments to target aging processes. Regulatory changes and further development of drugs is needed to make strides in improving human health. Meanwhile anti-aging therapies that are not regulated are avoided in worry they may cause more harm than help due to lack of clinical data support; this is the ever present challenge geroscientists and the anti-aging community have taken up in hopes of challenging traditional thinking and the aging process in the coming decades.

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