By David Blokh and Ilia Stambler

Summary

This article argues for the expanded application of information-theoretical measures, such as entropy and normalized mutual information, for research of biomarkers of aging and physiological age as an early predictive measure of age-related multimorbidity and frailty. The use of information theory enables unique methodological advantages for the study of aging processes, as it allows to evaluate non-linear relations between biological parameters, providing the precise quantitative strength of those relations, both for individual and multiple parameters, showing cumulative or holistic (synergistic) effects. The diagnostic models can be built based on diagnostic parameters routinely available to physicians (frailty indexes, laboratory analysis, physical evaluations) as well as more advanced biomarkers (e.g. genetic and epigenetic analysis) – in relation with age and age-related diseases and frailty. The diagnostic systems that are built in this way can be open and can include any number of additional parameters correlated with age and age-related diseases. The use of information-theoretical methods, utilizing normalized mutual information, can reveal the exact amount of information that various diagnostic parameters or their combinations contain about the persons’ physiological (or biological) age. Based on those exact diagnostic values for physiological age determination, it is possible to construct a diagnostic decision rule to evaluate a person’s physiological age, as compared to chronological age. The working hypothesis is that people characterized by higher physiological age will have increased risk of age-related frailty and diseases (e.g. heart disease, cancer, type 2 diabetes, neurodegenerative diseases, fractures, falls, mental and functional decline, etc.). Utilizing information-theoretical measures, with additional data, it may be possible to create further clinically applicable information-theory-based markers and models for the evaluation of physiological age, its relation to age-related diseases and its potential modifications by therapeutic interventions, such as medications and behavioral interventions.[1]

Introduction: The increasing need for anti-aging intervention and longevity medicine

With the rapidly growing aging population, and the corresponding rise in the incidence of aging-related diseases (such as heart disease, cancer, type 2 diabetes, neurodegenerative disease, chronic obstructive pulmonary diseases, etc), there emerges a special need to estimate health conditions and effectiveness of treatments for a variety of aging-related diseases, based on the evaluation of the aging processes underlying those diseases. Such evaluation is also needed to assess the effectiveness of potential anti-aging interventions and interventions against aging-related diseases. Even more importantly, it is needed for an early preventive intervention in these diseases, based on the calculated physiological age. The importance of quantifying the effects of “normal” aging as compared to “abnormal”, “pathological”, “accelerated” or “premature” aging cannot be overestimated. It is critically important to be able to diagnose “early aging”, that is, to identify subjects in whom “biological” or “physiological age” markedly exceeds the “chronological age”. Thanks to such “early diagnosis” of aging, as a pre-clinical or concomitant condition for a variety of aging-related diseases, it may be possible to solve the problems of early diagnosis of those aging-derived diseases. In other words, it may be stated that pre-clinical diagnosis of aging-related diseases (such as Alzheimer’s disease, type 2 diabetes, cancer and heart disease) naturally belongs in the field of aging research, as aging can be seen as a pre-symptomatic, pre-clinical root determinant of a variety of aging-related diseases.[2]

Cancer

Of special importance, early evaluation of physiological age may facilitate the early diagnosis of cancer with a prolonged preclinical period. This may considerably improve the efficacy of treatment for oncological diseases. There have been debates regarding the usefulness or lack thereof of mammography for subjects aged 40-49, that is regarding the possibility of preclinical diagnosis.[3] It may be difficult to solve this problem in the framework of pure oncology, disregarding the factors of age or aging, but only in the framework of aging research, for which information-theoretical analysis can be meaningfully applied.

Heart disease

The same may be said for cardiovascular diseases, the main age-related cause of death in the world, including deaths due to ischemic heart disease and ischemic and hemorrhagic stroke.[4] Yet, it is also known that cardiovascular diseases, and ischemic heart disease in particular, can be highly susceptible to therapeutic and lifestyle interventions, capable of dramatically extending the health and longevity of the subjects.[5] Hence it is of primary importance to be able to early assess the entire array of risk factors as well as the effects of therapeutic interventions on the risk factors, either individually or in combinations, including both biological and chronological age.[6]

Neurodegenerative diseases

Also for neurodegenerative diseases, such as Alzheimer’s disease, the vast plasticity of the brain of the aged and the feasibility of positive therapeutic interventions, or even cures, have been recognized. Yet, it has also been recognized that, in order to accomplish such interventions, the earliest possible detection and the consideration of polygenic etiologies will be necessary.[7] Here too information-theoretical statistics, capable of utilizing time series methods for prediction from an earlier, preclinical age, and employing mutual information measures to establish non-linear diagnostic correlations of multiple disease determinants, including age, can be indispensable.

Diabetes – Metabolic syndrome

Also, for type 2 diabetes, “diagnosis of aging” can be very helpful for early diagnosis of diabetes, as the diagnostic parameters relevant to diabetes, as well as the underlying biological mechanisms have a great similarity with “normal” aging.[8]

Frailty

Generally, the ability to reliably quantitatively diagnose “delayed aging” or “healthy aging” may pinpoint powerful factors facilitating healthy and productive longevity. Here “healthy aging” (or “healthy longevity”) may be understood as the absence of age-related frailty, as commonly defined in geriatric medicine, that is, an active and functional state of older adults characterized by a decreased risk for future poor clinical outcomes, diminished development of disability, dementia, falls, hospitalization, institutionalization or decreased mortality.[9] The ability to provide early quantitative evaluation of frailty risks is also of great medical and economic significance.

Prospective economic benefits from the early detection of aging-related diseases thanks to improved diagnosis of aging itself

The humanitarian and economic importance of early detection of aging-related diseases is obvious. Early detection makes it possible to apply preventive medical interventions when the disease is in a more manageable and even curable state, ideally even before any clinical manifestations, thus significantly postponing the time it may take for the disease to progress to a severe, debilitating and more costly state. This postponement of morbidity is also the reason for the vast economic benefits of early detection, necessary for the early preventive intervention. As shown for the US, patients with chronic age-related diseases expend in their last year of life about one third of the total Medicare expenditures (~$15,000 per person).[10] Any postponement of this high morbidity period thanks to early detection and preventive interventions can produce massive net health and economic benefits.

Some of the economic benefits of early detection derive from the improvement of individual health, averting direct medical costs and entitlement payments, reducing lost productivity, disability, and employee turnover.[11] As of 2004, it was estimated that “75 percent of the $1.9 trillion spent on health care in the United States stem from preventable chronic health conditions … but only 1 percent is allocated to protecting health and preventing illness.”[12]

Specifically, regarding particular aging related diseases, such as Alzheimer’s disease and Cancer, the savings from early detection per patient are commonly estimated at several thousand dollars for the developed countries — $1,000-10,000+ for Alzheimer’s disease,[13] $1,000-10,000+ for various forms of cancer.[11] Comparable savings can be expected from the early detection of heart disease[14] and diabetes.[15]

The numbers of patients suffering from these conditions globally are estimated at tens of millions, and are expected to strongly increase worldwide due to the rapid population aging.[16] Thus, 36 million people worldwide are living with dementia, including ~10M in Europe and ~5M in the US, with their numbers expected to double every 20 years, reaching 66 million by 2030, and 115 million by 2050.[13] Out of the total of 56 million deaths that occurred worldwide in 2012, about 38 million were due to non-communicable (NCD) aging-related diseases, in particular: cardiovascular diseases (17.5 million deaths, or 46.2% of NCD deaths), cancers (8.2 million, or 21.7% of NCD deaths), respiratory diseases, including asthma and chronic obstructive pulmonary disease (4.0 million, or 10.7% of NCD deaths) and diabetes (1.5 million, or 4% of NCD deaths).[17]

The costs of aging-related diseases worldwide are correspondingly vast, amounting to hundreds of billions and trillions of dollars: ~US$600 billion in 2010 only for dementia worldwide[13], approximately US$800 billion for heart disease; US$850 billion for type 2 diabetes; US$900 billion for cancer; US$300 billion for Chronic Obstructive Pulmonary Disease – COPD.[18]

Thus the healthcare benefits of even minor improvement in the ability of early diagnosis, necessary for early preventive treatments of aging-related diseases, could be immense. The economic benefits from the preventive approach, intervening in the aging processes underlying the non-communicable diseases before they take clinical forms, would be immense as well (hundreds of billions of dollars savings in health expenditures in the course of several decades just in the US, according to some models [19]). Yet, to accomplish this, improved diagnostic capabilities are needed for the aging process itself, capable to reliably estimate the person’s physiological and biological age and the effects of interventions on that age.

New methodologies are needed to provide early diagnosis of aging-related ill health

In view of the pressing global social need, new methodologies are required to enable early detection of aging-related ill health. We argue that information-theory-based approaches, utilizing such measures as entropy and mutual information, may provide powerful methodological tools for the solution of these problems. First of all, information theory may allow a more reliable estimation of biological and physiological correlates (biomarkers) of aging, due to its ability to estimate non-linear correlations between parameters, utilizing mutual information measures. The a priori reliance on linear statistical correlations when trying to determine such biomarkers has been failing to produce practically applicable results.[20] [21] Information-theoretical measures may provide new means to intensify and facilitate this search. Moreover, the preclinical diagnosis requires the simultaneous analysis of a large number of parameters of various kinds, including continuous parameters, with both Gaussian and non-Gaussian distribution, as well as discrete and ranked parameters. Presently, the only theoretically grounded method for the simultaneous analysis of multiple parameters of different kinds is information theory..[22]

Advantages of the information-theoretical methodology

Arguably, it is methodologically problematic to use the current approaches in biomarkers research and quantified health for practical assessments of physiological age and potential aging-ameliorating and healthspan-extending interventions. The methodological difficulties may derive from two major current shortcomings. Firstly, the current approaches, both in quantified health and biomarkers research, are mainly based on static or short term, average or median population values to define the norm. This makes personalization of clinical evaluations and treatments difficult. Secondly and crucially, the existing approaches commonly assume normal (Gaussian) distribution and linear relations of parameters. Hence, they mainly employ linear statistical measures of correlation, such as the correlation coefficient or linear regression. However, such measures do not correspond to physiological realities, where the relations between parameters are non-linear, including the non-linear alterations with age. Hence the currently used methods are ill suited to evaluate physiological age and aging-ameliorating and healthspan extending interventions. The main advantage of the information-theoretical methodology is that it provides an integrated approach that will take into consideration the non-linear interrelation of a multitude of parameters – biomarkers and intervention factors, using information theoretical measures rather than linear statistical measures.[1]

Information theory can serve as a universal methodology to assess health and disease status, in relation to age, unifying a variety of model systems, focusing on age-related changes as the root cause of a variety of chronic age-related diseases and health impairments. Information theory may provide the following specific methodological capabilities, currently not available in any other system:

• The current health metrics mainly employ statistical measures. Yet, statistical measures are often inadequate, insofar as in biological systems, the relations between parameters are often non-linear. In contrast, information-theoretical methods allow for the estimation (measurement) of complex non-linear relations between parameters, hence they allow for the inclusion of a wider range of data for making health decisions.
• Currently, the results from different study models are described in incompatible terms, that do not permit an easy mutual inference. In contrast, the common terms and measures of information theory, such as entropy and mutual information, can serve as a universal language to describe, in a unified way, any number of diverse models and results.
• Currently, the degree of mutual applicability between animal model systems and humans, as well as between diverse human samples, is uncertain.  In contrast, the evaluation of mutual information between different model systems, can be used as a standardized and convenient estimate of their mutual applicability.
• Currently, the effects of various treatments on human health are often examined in a disconnected manner, without knowing the precise interactions of various treatments. The information-theoretical measures of correlation (such as normalized mutual information) can be employed to test the effects of single or combinations of various treatment factors (such as drugs, genes and lifestyle factors) on the health span and the disease status. By the precise quantitative evaluation of the influence of such factors on the health span and disease status, both synergistic positive and antagonistic adverse effects of treatment interactions will be determined.
• The current systems lack the formal ability to select the most informative (and hence clinically useful) parameters. Using information-theoretical methods, the most informative single parameters or groups of parameters with the highest influence on the health span and disease status can be selected. The selection of the most informative parameters, such as those that contain information about other selected parameters, will allow for a more economic, convenient and efficient diagnostic system. This will save time and expenditures on unnecessary testing, by eliminating the less informative parameters from the outset.
• The current statistical systems are largely heuristic. In contrast, in the information-theoretical diagnostic systems, mutual information is able to provide the exact estimate of similarity between various model systems. Therefore it may be possible to predict the efficacy of a yet untested drug or treatment using the estimates of its similarity (mutual information) with other tested drugs and treatments along with the similarity of model systems to which they are applied. Such an approach may save on unnecessary animal and human testing and facilitate the development of new drugs and treatments.
• The current health assessment systems lack a unified standard or frame of reference. The information-theory-based combined metrics for measuring health status may be based on the convenient and standardized evaluation of system stability, using information-theoretical measures, such as entropy and mutual information. The current systems are mainly based on static, average or median population values. The proposed information-theoretical measures of system stability, assessing dynamic changes in a particular system, can be self-referential, and hence truly personalized.
• The current systems do not permit formal assessment of system stability due to treatments. In contrast, information theory may permit to estimate the effects of particular drugs and treatments, or their combinations, on the stability of a particular system for the short and/or long term, by calculating the system alterations at the input and output caused by the particular treatments. This may provide a common measure of health status and effects of interventions, for the short and long term.

These capabilities are based on the known abilities of information theory, such as 1) to estimate non-linear relations; 2) to describe diverse systems in common terms of entropy change; 3) to estimate the degree of similarity or difference between various systems; 4) to examine combined effects of different parameters on a parameter of choice; 5) to select the most informative parameters; 6) to predict outcomes, as was shown by the wide use of information theory in diagnosis, especially of age related diseases,[1] including cancer;[23] 7) to estimate the general system stability [22]; 8) to estimate changes in system stability, heterogeneity, regulation and information loss in response to external stimuli.

Sample selection

A critical requirement for building an information-theoretical diagnostic model of physiological age and aging-related diseases is the availability of a large range of clinical and biological data on a large population sample. The data can be as diverse as possible, any data may be of interest.. The more data is available and the more diverse it is, the more interesting correlations may be discovered and the better may be the diagnostic power. The data may include biomarkers of aging and the types of data that are commonly used in quantified health applications. For example, cellular, molecular and biochemical markers for biological age may include: age-related changes in telomere length (telomere measurement), advanced glycation endproducts (AGE), 8-hydroxyguanine in DNA and amino acids with oxidized side chains as biomarkers of oxidative stress, levels of proteins that are essential for critical functions, DNA repair capacity, decrease in one or more stem cell populations, T-lymphocyte subsets, gene expression micro-array analysis (e.g. for such genes as Sirtuins, Foxo, Clotho, etc.), epigenetic markers (e.g. methylation), measures of oxidative-reductive and acid-base balance, and more. Furthermore, functional markers for aging may include: muscle strength (manual muscle-testing; dynamometer: hand-grip strength), vascular rarefaction and dysfunction (capillaroscopy; forearm blood flow techniques), gait speed, step-to-step variability, balance, functional mobility (timed-up-and-go), endurance capacity (VO2 max), cardio-respiratory indicators (PaO2; PaO2/FiO2), EEG/ECG/EMG, nutritional state/intake, cognition (tests), psychological type profiling (tests), social participation, socio-economic status (income, employment).

Diverse therapeutic influences may be factored into the model in order to evaluate the efficacy of potential aging and lifespan improving interventions and their effects on the biological, physiological and functional age.[24] Those interventions may include: pharmacological treatments (specific drugs, such as rapamycin, metformin, statins, aspirin, etc.), regenerative cell therapies, specific biomedical interventions (operations, physiotherapeutic techniques), reduction of risk factors (smoking, alcohol consumption), dietary factors (e.g. supplements, nutrients, functional foods), physical activity, exercise, rest and sleep, education.

Thus, thanks to the diversity of modeled parameters, various factors affecting aging – biological, environmental and social – can be inter-related and integrated. (Of course, the costs of particular markers is an important consideration, hence it may become preferable, at least for practical applications, to use such parameters that would be routinely and inexpensively available to practicing physicians. Notably, however, the number of parameters and the amounts of data, collected, analyzed and made available to physicians and researchers, are constantly and rapidly increasing.)

Another issue in selecting data to construct a diagnostic model for physiological age and aging-related ill health is the fact that there is currently no clear, formal and universally accepted clinical definition of aging that can serve as the basis for diagnosis and therapy, which can formally and reliably distinguish between “pathological/accelerated aging” as opposed to “healthy aging”. Not surprisingly, the World Health Organization’s “Global Strategy and Action Plan on Ageing and Health” (2015) includes “Strategic objective 5 – “Improving measurement, monitoring and research on Healthy Ageing” including such priority tasks as “Develop norms, metrics and new analytical approaches to describe and monitor Healthy Ageing” and “Develop resources, including standardized survey modules, data and biomarker collection instruments and analysis programs.”[25] Such a formal understanding and measurement of healthy aging can be aided thanks to the use of standard information-theoretical measures.

An additional important issue for the diagnostic model construction may be the choice of subjects and samples. Arguably, it is preferable to rely on the long-term (longitudinal), rather than short-term (immediate benefit) analysis. Thus it may be desirable to consider a large number of medical histories of people who were 67-70 a couple of decades back (say in 1990 for illustration) and who were at that time considered “clinically” healthy. From this set, we can form two subsets:

1. The set of medical histories of people who died in 1990-1995, at the age of 67-75 years, from various aging-related diseases, such as type 2 diabetes, cancer, heart disease and Alzheimer’s disease.
2. The set of medical histories of people, who are alive presently (in 2017). These persons are at the time 94-97 years old. We assume that the second subset is characterized by greater resilience or delayed aging as compared to the first set. Despite the potential issues on incomplete data and changing measurement techniques, the use of such a sample selection allows us to solve the following problems:
3. To quantitatively determine the risk factors, related to the emergence and course (severity) of the aging-related diseases: diabetes, cancer, heart disease and Alzheimer’s disease.
4. To quantitatively determine the influence of those factors on the emergence and course of the diseases.
5. To quantitatively estimate the combined influence of groups of factors on the diseases and reveal the factors producing cumulative effects.
6. To construct algorithms of pre-clinical diagnosis of the aging-related diseases, such as diabetes, cancer, heart disease and Alzheimer’s disease.

For the solution of each of these problems, out of the two subsets, it may be possible to select further subdivisions corresponding to the particular diagnostic tasks at hand. Such a two-fold sample set may also allow the researchers to quantitatively and formally investigate the process of aging, as an underlying and common factor of these diseases, by utilizing the multi-factorial model which corresponds to the understanding of aging as a complex process depending on multiple factors of different etiology. In other words, rather than attempting to infer from the poorly defined concept of biological aging toward its derivative conditions (diseases), it may be possible to formally define pathological or early aging from these diagnosable conditions, seeking common age-related denominators between them.

It should be noted that information-theoretical models of physiological age and aging-related ill health do not need to restrict themselves from the outset to any particular kinds of parameter data or hypothesis. The information theoretical approach may allow the research to utilize any kind of data, at any level, into a single diagnostic model. Thus it can, for example, combine diverse biochemical, molecular-biological, cellular, tissue, physiological, functional and other parameters related to aging. Thus the more parameters of different kinds the researchers may be able to obtain, and the larger the investigated sample they will be able to obtain – the stronger and more informative the model will be. Yet, for practical concern, and at the initial stages, it may be preferable to strive to first utilize the parameters commonly used in the clinic, such as blood work (biochemistry and cytology). It should also be noted, that the choice of the 2 subsets, as indicated above, is not restrictive either. The two subsets allow the convenient primary distinction between subjects presumably characterized by different levels of resilience in aging. Yet, with the addition of more age cohorts, including the young (e.g. across several decades of life) – the diagnostic capabilities may be improved, depending on the availability of data.

Even though the information-theoretical approach can incorporate any number of subjects into the model, improving its diagnostic capabilities, at the initial stage it may be desirable to analyze data from at least 2000 subjects, say 1000 from each subset, as this number of subjects is a putative desirable requirement to establish combined diagnostic indicators from 3 or 4 different parameters. The following rule of thumb can be applied for the selection of the sample size: In the analysis of tables of conjunction, we assume that for almost all the cells, the expected number of elements should be no less than 5 in each cell.[26] We consider discrete parameters that can assume 3 values (i.e. below, equal or above some normative of delimiting value). The rule of thumb, to fulfill the sufficiency criteria for the estimation of the sample size, is: the number of cells in the conjunction matrix (say 9 for 2 parameters – 3×3) x 5 (5 elements in each cell) x 5 (to increase the probability that there will be 5 elements in each cell, though this latter number can be more). Thus for a correlation between 2 single parameters, it is 9x5x5=225 (~200-250), for a correlation of 2 parameters with a third one: 27x5x5=675 (~500-700), for a correlation of 3 combined parameters with a fourth one: 81x5x5=2025 (~2000), etc. 2000 subjects is also the typical number involved in FDA phase 3 clinical trials.[27] However, with further increasing the sample size, the diagnostic value will be further increased. The sample sizes will also depend on the nature of the relations examined. For example, when the parameters are strongly mechanistically related, the sample size could be less. And once again, costs of analysis need to be considered, obviously increasing with a greater sample size.

Evaluation of age-related multimorbidity

Using information-theoretical methodology, it may be possible to establish diagnostic decision rules not just for individual diseases, or for physiological age, but also for combined age-related diseases (age-related multimorbidity). Out of several individual disease variables, a single “multimorbidity” variable can be established composed of several diseases (e.g. diabetes and heart disease and dementia, etc.). And this new composite variable can be correlated to individual or combined risk factors by normalized mutual information. Based on the values of normalized mutual information (strength of correlations), the decision rule could be constructed for the entire multimorbidity variable, or for different types of multimorbidities.

The added value and even necessity of estimating physiological age and age-related multimorbidity, in addition to diagnosing individual diseases, is due to the following reasons:

• Chronological and Physiological Age are necessary for diagnosis. It is necessary to accomplish early diagnosis also for individual diseases. The degenerative aging process is the main contributor to age-related diseases. Hence, not being able to evaluate it, discards one of the main, most informative diagnostic parameters. Moreover, the corresponding inability to intervene into degenerative aging, discards one of the most promising therapeutic targets.
• There is a need for integrative, time-related approach. Evaluation of only single diagnostic parameters and risk factors, or only single diseases, without their connection to each other and to the patients’ age, without considering their dynamic changes in time, their long term and synergistic effects, can produce misleading results in diagnosis, and ineffective and even unsafe therapy. The various diagnostic parameters, including age and period, should be evaluated together and intervened together.
• Evidence based criteria for physiological age and multimorbidity are needed to develop new therapies and interventions. Establishing quantitative and holistic criteria for healthy aging/longevity can help develop new therapies. The currently existing therapies and interventions are not always effective. There is a critical need to advance novel biomedical research of aging and aging-related diseases, to develop and test new treatments, to improve the healthspan of the elderly. The development of diagnostic criteria for healthy longevity (healthspan), like physiological age or multimorbidity, can help gauge the effects of new treatments and interventions.

It is hoped that information-theoretical methodology will contribute to the advancement of these tasks.

References and notes

[1]           David Blokh, Ilia Stambler, “Estimation of heterogeneity in diagnostic parameters of age-related diseases,” Aging and Disease, 5, 218-225, 2014, http://www.aginganddisease.org/EN/10.14336/AD.2014.0500218.

David Blokh, Ilia Stambler, “Information theoretical analysis of aging as a risk factor for heart disease,” Aging and Disease, 6, 196-207, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2014.0623.

David Blokh, Ilia Stambler, “Applying information theory analysis for the solution of biomedical data processing problems,” American Journal of Bioinformatics, 3(1), 17-29, 2015, http://thescipub.com/abstract/10.3844/ajbsp.2014.17.29.

David Blokh, Ilia Stambler, “The application of information theory for the research of aging and aging-related diseases,” Progress in Neurobiology, S0301-0082(15)30059-9, 2016, doi: http://dx.doi.org/10.1016/j.pneurobio.2016.03.005.

David Blokh, Ilia Stambler, “The use of information theory for the evaluation of biomarkers of aging and physiological age,” Mechanisms of Ageing and Development, S0047-6374(16)30156-7, 2017, doi: http://dx.doi.org/10.1016/j.mad.2017.01.003.

[2]           Michael J. Rae, Robert N. Butler, Judith Campisi, Aubrey DNJ de Grey, Caleb E. Finch, Michael Gough, George M. Martin, Jan Vijg, Kevin M. Perrott, Barbara J. Logan, “The demographic and biomedical case for late-life interventions in aging,” Science Translational Medicine, 2, 40cm21, 2010, http://stm.sciencemag.org/content/2/40/40cm21.full.

Luigi Fontana, Brian K. Kennedy, Valter D. Longo, Douglas Seals, Simon Melov, “Medical research: treat ageing,” Nature, 511(7510), 405-407, 2014.

Kunlin Jin, James W. Simpkins, Xunming Ji, Miriam Leis, Ilia Stambler, “The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population,” Aging and Disease, 6, 1-5, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2014.1210.

Ilia Stambler, “Recognizing degenerative aging as a treatable medical condition: methodology and policy,” Aging and Disease, 8(5), 2017, http://www.aginganddisease.org/EN/10.14336/AD.2017.0130.

Ilia Stambler, “Human life extension: opportunities, challenges, and implications for public health policy,” in Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 535-564, http://pubs.rsc.org/en/content/ebook/978-1-78262-435-6#!divbookcontent.

[3]           Bonnie N. Joe, “Risk-based screening misses breast cancers in women in their forties,” Radiological Society of North America, 2014, retrieved from: http://www.rsna.org/.

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[4] Rafael Lozano, et al. (189 authors), “Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010,” Lancet, 380, 2095-2128, 2012.

[5]           Judith Meadows, Jacqueline Suk Danik, Michelle A. Albert, “Primary prevention of ischemic heart disease,” in: Elliott M. Antman (Ed.), Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease, Third edition, Saunders Elsevier, Philadelphia PA, 2007, pp. 178-220.

[6]           David Blokh, Ilia Stambler, “Information theoretical analysis of aging as a risk factor for heart disease,” Aging and Disease, 6, 196-207, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2014.0623.

[7]           Zaven S. Khachaturian, “Perspectives on Alzheimer’s disease: past, present and future,” Advances in Biological Psychiatry, 28, 179-188, 2012.

[8]           David Blokh, Ilia Stambler, “Estimation of heterogeneity in diagnostic parameters of age-related diseases,” Aging and Disease, 5, 218-225, 2014, http://www.aginganddisease.org/EN/10.14336/AD.2014.0500218.

Diane Chau, Steven V. Edelman, “Clinical management of diabetes in the elderly,” Clinical Diabetes, 19, 172-175, 2001.

[9]           Linda P. Fried, Jeremy Walston, “Frailty and failure to thrive,” in: William R. Hazzard, John P. Blass, Walter H. Ettinger, Jeffrey B. Halter, Joseph G. Ouslander (Eds.), Principles of Geriatric Medicine and Gerontology, 4th Ed., McGraw Hill, New York, 1999, pp. 1387-1402.

[10]          Amber E. Barnato, Mark B. Mcclellan, Christopher R. Kagay, Alan M. Garber, “Trends in inpatient treatment intensity among medicare beneficiaries at the end of life,” Health Services Research, 39(2), 363-376, 2004.

[11]          C-Change: Collaborating to Conquer Cancer, Making the Business Case: How Engaging Employees in Preventive Care Can Reduce Healthcare Costs, 2008, http://c-changetogether.org/Websites/cchange/images/Risk_Reduction/C-Change_Business_Case_White_Paper_(1).pdf.

[12]             National Committee for Quality Assurance, Executive Summary. The State of Health Care Quality 2004, National Committee for Quality, Washington DC, 2005, quoted in: C-Change: Collaborating to Conquer Cancer, Making the Business Case: How Engaging Employees in Preventive Care Can Reduce Healthcare Costs, 2008, http://c-changetogether.org/Websites/cchange/images/Risk_Reduction/C-Change_Business_Case_White_Paper_(1).pdf.

[13]          Alzheimer’s Disease International, World Alzheimer Report 2011. The benefits of early diagnosis and intervention, Martin Prince, Renata Bryce, Cleusa Ferri (Eds.), Institute of Psychiatry, King’s College, London, 2011, https://www.alz.co.uk/research/world-report-2011.

[14] National Association of Chronic Disease Directors, “Why we need public health to improve healthcare,” 2015, http://www.chronicdisease.org/?page=WhyWeNeedPH2impHC.

[15]         WHO Media Center, “Diabetes: the cost of diabetes,” Fact sheet N°236, 2015, http://www.who.int/mediacentre/factsheets/fs236/en/.

[16]          Stephen S. Lim, et al., “A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010,” Lancet, 380, 2224-2260, 2012;

Rafael Lozano, et al., “Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010,” Lancet, 380, 2095-2128, 2012.

[17]          World Health Organization, Global Status Report on Noncommunicable diseases 2014, http://www.who.int/nmh/publications/ncd-status-report-2014/en/.

[18] David E. Bloom, et al., The Global Economic Burden of Non-Communicable Diseases: A report by the World Economic Forum and the Harvard School of Public Health, World Economic Forum, Geneva, 2011, http://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf .

[19]          Dana P. Goldman, David M. Cutler, John W. Rowe, Pierre-Carl Michaud, Jeffrey Sullivan, Jay S. Olshansky, Desi Peneva, “Substantial health and economic returns from delayed aging may warrant a new focus for medical research,” Health Affairs, 32(10), 1698-1705, 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938188/;

Dana P. Goldman, “The economic promise of delayed aging,” in: Stuart Jay Olshansky, George M. Martin, James L. Kirkland (Eds.), Aging: The Longevity Dividend, Cold Spring Harbor Laboratory Press, 2016.

[20]          Robert N. Butler, Richard Sprott, Huber Warner, Jeffrey Bland, Richie Feuers, Michael Forster, Howard Fillit, S. Mitchell Harman, Michael Hewitt, Mark Hyman, Kathleen Johnson, Evan Kligman, Gerald McClearn, James Nelson, Arlan Richardson, William Sonntag, Richard Weindruch, Norman Wolf, “Biomarkers of aging: from primitive organisms to humans,” Journal of Gerontology. A. Biological Sciences Medical Sciences, 59, B560-567, 2004.

[21]          Arthur K. Balin (Ed.), Practical Handbook of Human Biologic Age Determination, CRC Press, Boca Raton FL, 1994.

[22]          David Blokh, Ilia Stambler, “The application of information theory for the research of aging and aging-related diseases,” Progress in Neurobiology, S0301-0082(15)30059-9, 2016, doi: http://dx.doi.org/10.1016/j.pneurobio.2016.03.005; http://www.sciencedirect.com/science/article/pii/S0301008215300599.

[23] David Blokh, Elena Afrimzon, Ilia Stambler, Eden Korech, Yana Shafran, Naomi Zurgil, Mordechai Deutsch, “Breast cancer detection by Michaelis-Menten constants via linear programming,” Computer Methods and Programs in Biomedicine, 85, 210-213, 2006;

David Blokh, Ilia Stambler, Elena Afrimzon, Yana Shafran, Eden Korech, Judith Sandbank, Ruben Orda, Naomi Zurgil, Mordechai Deutsch, “The information-theory analysis of Michaelis–Menten constants for detection of breast cancer,” Cancer Detection and Prevention, 31, 489-498, 2007;

David Blokh, Naomi Zurgil, Ilia Stambler, Elena Afrimzon, Yana Shafran, Eden Korech, Judith Sandbank, Mordechai Deutsch, “An information-theoretical model for breast cancer detection,” Methods of Information in Medicine, 47, 322-327, 2008;

David Blokh, Ilia Stambler, Elena Afrimzon, Max Platkov, Yana Shafran, Eden Korech, Judith Sandbank, Naomi Zurgil, Mordechai Deutsch, “Comparative analysis of cell parameter groups for breast cancer detection,” Computer Methods and Programs in Biomedicine, 94, 239-249, 2009.

David Blokh, “Information-theory analysis of cell characteristics in breast cancer patients,” International Journal on Bioinformatics & Biosciences (IJBB), 3 (1), 2013.

[24]          Imre Zs.-Nagy, Denham Harman, Kenichi Kitani (Eds.), Pharmacology of Aging Processes: Methods of Assessment and Potential Interventions, Annals of the New York Academy of Sciences, Volume 717, 1994;

Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017.

[25]         World Health Organization, Global Strategy and Action Plan on Ageing and Health, World Health Organization, Geneva, November 2015, http://who.int/ageing/global-strategy/en/.

[26] Solomon Kullback, Information Theory and Statistics, John Wiley & Sons, New York, 1958;

John H. Pollard, A Handbook of Numerical and Statistical Techniques. With Examples Mainly From The Life Sciences, Cambridge University Press, Cambridge, 1977.

[27] US Food and Drug Administration, “The Drug Development Process. Step 3: Clinical Research,” accessed March 2017, http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm.

By Ilia Stambler

Introduction

Various means of therapeutic interventions into degenerative aging processes are now gaining increasing interest. The interest is largely due to the mounting challenges of the rapidly aging world population and the correspondingly increasing desire to seek solutions.[1] Yet, when searching for means to intervene into degenerative aging processes, the emphasis is often placed either on traditional means of life-style improvement (rest, exercise, moderate and balanced nutrition) or various pharmacological means (the so-called geroprotective or anti-aging drugs)[2] or gene-therapeutic or cell-therapeutic means (the so called regenerative medicine).[3] Yet, additional classes of potential interventions may be possible. Anti-aging and life-extending interventions do not necessarily need to be behavioural, biochemical or biological, but can also be physical, in particular as relates to various resuscitation technologies for the elderly, for example hypothermia and suspended animation,[4] electromagnetic stimulation,[5] or oxygenation (also in a sense a “biochemical” intervention, but with a stronger emphasis on physical energy metabolism and physical properties, such as gas pressure). Such technologies represent some of the most veritable means for life extension, demonstrably saving people from an almost certain death. But similar principles could perhaps be used for more preventive treatments and in less acute cases.

This work will focus on means of oxygenation, in particular hyperbaric (high pressure) oxygenation. It may be stated that 100% cases of death, including aging-related deaths, ultimately are caused by a lack of oxygen supply. Hence, various means of oxygenation may be considered as anti-aging means. On the other hand, oxidative damage has been long associated with the aging process.[6] From early times, human life has been likened to a burning candle: too much and too fast burning (oxygenation) could lead to an early death.[7] Hence efficient oxygen supply management may be needed to maintain healthy longevity. This article draws attention to the issue of oxygenation, in particular the use of hyperbaric oxygen therapy. It is not intended as a clinical guideline, but as a reflection on a potentially important issue and an invitation for further consideration of physical, energy-modulating means for anti-aging and life-extension, in particular oxygen management by such means as hyperbaric oxygenation therapy.[8] Some other physical means, such as temperature manipulation and electromagnetic stimulation, are also briefly considered with the same purpose to stimulate further interest.

The use of hyperbaric oxygen against acute and chronic diseases

Insofar as many (perhaps ultimately all) of the cases of death are ultimately due to various forms of oxygen deficit, a powerful means of life extension may be by improving oxygen supply. One form of oxygen supply can be in the form of Hyperbaric Oxygenation (using Oxygen Pressure Chamber or Barochamber). Such therapy was indicated as beneficial against a variety of life-threatening acute conditions, such as traumas and injuries, including severe brain and chest injuries, and could also improve a variety of degenerative and aging-related conditions, from neurological impairments, such as cerebral palsy and strokes, to diabetes.[9]

However, in high concentrations, oxygen can be cytotoxic. On the positive side, oxygen toxicity against bacteria may partly explain beneficial effects of hyperbaric oxygenation for treating acute infections, as well as wound, burn and fracture healing, where infections can be a major obstacle to effective healing.[10] The cytotoxic effects may be also involved in anti-cancer treatment, to destroy cancer cells by high oxygen concentrations.[11] Yet, the oxygen cytotoxic effect can be problematic, when either the oxygen dose or time of exposure to oxygen exceed a desirable physiological threshold.[12] Oxygen can lead to excessive cell and tissue stimulation, exhausting cell replicative potential, increasing the amount of reactive oxygen species and hastening the transition to apoptotic cell death via mitochondria activation.[13] The thresholds of oxygen toxicity have been uncertain even regarding single time applications of hyperbaric oxygenation.[14] And long-term effects of hyperbaric oxygenation on human life span apparently have not been studied.

Mechanisms of action of hyperbaric oxygenation against aging-related conditions

The mechanisms of potential general protective and/or anti-aging (geroprotective) effects of hyperbaric oxygenation, if such are indeed present, are yet to be elucidated. The question of dosages may be also crucial for determining the mechanisms of such anti-aging effects. High dosages of hyperbaric oxygen should intuitively induce oxidative stress, with high reactive oxygen species (ROS) production, which has been long seen as one the major sources of molecular damage in aging.[6] Indeed, oxidative damage has been observed under hyperbaric oxygen treatment, among other effects potentially contributing to cataract development.[15] Yet, it is also appreciated that, at certain levels, ROS may stimulate tissue regeneration.[16] And yet at certain dosages, hyperbaric oxygen may produce stimulatory “hormetic” effects (i.e. stimulation by a low dose, as opposed to inhibition by a high dose of the same factor), which may in fact increase anti-oxidant protection, via stimulation of anti-oxidant defense systems.[17] The protective effects of hyperbaric oxygen by stimulating heat shock protein expression[18] and stem cell mobilization[19] have also been suggested. In a related way, chronic systemic inflammation has been long implicated as a major source of aging-related damage.[20] Furthermore, excessive neuro-inflammation has been a sustained therapeutic target.[21] Hyperbaric oxygenation has been commonly reported to produce an anti-inflammatory effect, which has been suggested as one of its major therapeutic mechanisms, for both age-related chronic and acute conditions (like acute ischemic stroke).[22] Yet, there is also a growing realization that pro-inflammatory effects may be essential for tissue regeneration, including neuro-regeneration.[23]

Closely related to the phenomenon of hormesis (low dose stimulation), hyperbaric oxygenation may exert protective anti-ischemic effects through ischemic preconditioning, that is applying a certain sub-threshold dosage of hyperbaric oxygen that would induce a transient, mild ischemia that would confer tolerance to subsequent, more severe ischemia.[24] This mechanism opens the possibility for using hyperbaric oxygenation as a preventive therapy for the elderly. Some of the mechanisms of preconditioning were associated with enhanced expression of protective enzymes, such as Sirtuins,[25] enhanced Mitogen-activated protein kinases (MAPKs) and autophagy[26] and inhibiting the mTOR pathway.[27] Thus, the mechanisms of preconditioning by hyperbaric oxygenation may be similar with the application of other geroprotective medicines (e.g. Sirtuin-stimulating or mTOR inhibiting drugs),[28] producing a general improvement of energy metabolism, yet potentially with fewer pharmacogenic side effects. However, this possibility will yet require extensive investigation, necessitating a very careful consideration of the dosages. The short vs. long term effects should be considered when studying the mechanisms of action of hyperbaric oxygenation.[29] Indeed, there may be a need for a systemic, long term evaluation of oxygen therapy effects, as a part of a whole-organism whole-life-course model of energy resources expenditures. Such models are currently only emerging,[30] and are in great need of elaboration, both experimental and theoretical.

Supplementing Hyperbaric Oxygenation with additional treatment modalities

Hyperbaric Oxygenation can be seen as a potentially effective therapeutic or stimulating means, but it is unclear to which extent it can serve as a lifespan-extending means. Hence, the therapeutic modality of Hyperbaric Oxygenation may be supplemented or followed by additional modalities particularly designed to serve life-prolonging, rejuvenative and reparative functions. Pressure chamber could in principle provide a convenient environment to implement such modalities, insofar as it provides a protected, isolated and enclosed space unit, which can be easily manipulated and monitored for a variety of purposes. Some of the potential reparative applications can be as follows.

O2/CO2 Balance

For the life-span and health-span extension, rather than applying hyperbaric oxygenation, actually reducing oxygen partial pressure may be beneficial. Thus people living at high altitudes (with reduced oxygen pressure) are noted for high longevity, presumably due to either reduced metabolic rate or long-term adaptations. Some of the potential beneficial adaptations may include increased production of red blood cells, formation of new capillaries and increase in respiratory enzymes, and other mechanisms.[31]

Also, increased CO2 can be beneficial, insofar as persistent hypercapnia (enhanced CO2 level) has been associated with an increased life-span in animal models. This may presumably be due to increasing blood alkalinity (through liberating bicarbonate reserves) which may in turn positively affect proteins’ isoelectric stability.[32]

Interestingly and seemingly paradoxically, both hyperbaric oxygenation therapy and its apparent opposite – therapeutic hypoxia or hypoxic training (for example intermittent hypoxia) have been suggested to produce positive preconditioning effects against ischemic aging-related conditions, such as heart disease and neurodegenerative diseases.[33] The apparent paradox may be once again explained by the phenomenon of “hormesis” – namely the activation of anti-hypoxic/anti-ischemic protective mechanisms by certain extents of both deficit and excess of oxygen (in the latter case possibly increasing reactive oxygen species levels to induce a protective counter-effect), as well as possibly by other mild stressors (chemical, mechanical or electrical). The precise dosages and thresholds of such similar protective effects by seemingly diverse means, as well as their potential common central neuro-humoral regulatory mechanisms, yet require elucidation.

Besides hyperbaric oxygen therapy, normobaric (normal pressure) oxygen therapy, or just oxygen therapy generally (increasing oxygen supply) has been a widely applied means of therapy and resuscitation.[34] While hyperbaric oxygenation (using a pressure chamber) may be more effective to achieve rapid oxygen delivery to deep vital tissues, normobaric oxygenation (e.g. using an oxygen mask) may be more conveniently applicable and less expensive. Yet for normobaric oxygenation too, the appropriate balance of O2/CO2 levels may be critical. The pressure chamber may provide an ideal environment to control both O2 and CO2 levels and pressures, for acute therapeutic or prolonged restorative regimens. Still, with regard to CO2 manipulation, its long term effects as well as its effects on immediate daily performance will yet need to be established.

The issue of optimal thresholds or O2/CO2 balance will be vital, insofar as excessive O2 application may lead to a “burnout,” while excessive CO2 application may lead to a “death zone.” Both acidosis and alkalosis may be produced by O2/CO2 imbalance. Perhaps the most beneficial therapeutic regimen may be maintaining and/or rapidly restoring the physiological O2/CO2 balance. The normal (balanced) concentration of alveolar CO2 is often assumed to be about 6.5%, yet may vary according to particular metabolic requirements of every individual.[35]

Monitoring

In order to personalize the therapy, and to ensure its safety and efficacy, the treatment modalities should be related with a thorough array of monitoring and evaluation modalities, in particular for the evaluation of the organism’s energy metabolism, before, during and after the treatment. In performing oxygen therapy (in particular hyperbaric oxygenation), reference need to be made for Oxygen and CO2 balance (supply vs. demand), as well as for the supply and demand of macroergic (energy-rich) substances, in the entire organism and particular organs.[36] Measurement modalities may include oxygen measurement by mitochondrial cytochrome a,a3 reflectance spectrophotometry, mitochondrial NADH redox state by NADH fluorometry, tissue blood flow by Laser Doppler Flowmetry, hemoglobin oxygen saturation by reflectometry, DC potential and various ionic levels by micro-electrodes, gas partial pressure (O2, CO2, NO, etc) and pH levels by micro-electrodes and optodes, up to more advanced methods such as functional magnetic resonance imaging (fMRI) or using sequential single photon emission computerized tomography (SPECT) scans, etc.[37]

The monitoring of the gas composition (PaO2 and PaCO2) of the arterial blood may be seen as a necessary condition to perform effective hyperbaric oxygen therapy against life-threatening situations in patients with deteriorating cardiorespiratory functions, especially for the elderly patients.[8] This is necessary in order to control and maintain adequate levels of lung gas exchange, with regulated parameters of oxygen supply and controlled oxygen concentration. The speed of the blood flow and blood pressure in vital organs are also among the critical vital signs that need to be known. The basic parameters of cardiorespiratory function need to be monitored, such as: PaO2 mmHg – arterial partial pressure of oxygen; PaCO2 – arterial partial pressure of CO2; PaO2/FiO2 – the ratio of the partial pressure of oxygen to the fraction of inspired oxygen; SVI ml/m2 – stroke volume index; CI L/min/m2 – cardiac index; pH – blood acidity level. Such measures of cardio-respiratory function can help reference the normal balanced O2/CO2 levels in the blood and favorable blood electric charge and hemodynamic conditions.

The anatomical and physiological effects of aging on the heart and lungs are also vitally important parameters, including such indicators as the rise of arterial pressure and resistance with aging due to the increasing arterial stiffness, reduced contractility and relaxation of the heart, a reduction of lung vital capacity, impairment of gas mixture in the lungs, and other harmful anatomical and physiological effects of aging. All the deteriorative changes in the cardio-respiratory system generally show in the reduction of maximal oxygen uptake (VO2max) which has been considered one of the most informative parameters for biological age evaluation.[38]

The above parameters of cardiorespiratory function are practically indispensable in emergency and intensive care medicine, when treating acute and often life-threatening conditions. Yet, arguably, the cardio-respiratory parameters routinely employed in emergency and intensive care medicine may be good candidates for biomarkers of aging as they have proved their utility as real-time indicators of the organism’s vitality and energy. Often, in general frailty assessments, energy levels in the elderly are evaluated simply by asking the question “Do you feel full of energy?”[39] Yet, there may be more objective measures of the aging organism’s energy level, by such means as spirometry, oximetry, hemodynamic, electrochemical and spectroscopic energy metabolite measurements, as well as other structural and functional parameters of the cardiorespiratory system, that can provide improved indication for therapy.[40] Arguably, such cardio-respiratory “physiomic” parameters or markers of aging may be clinically valuable and conveniently interpretable for a practicing physician, alongside the many “biomarkers of aging” based on predominantly molecular-biological, e.g. genetic, epigenetic and other “omic” age-related alterations that are currently investigated. [41]

The main clinical utility of biomarkers or diagnostic parameters of aging is that their changes can help evaluate the effectiveness of particular therapeutic regimens, especially the effectiveness of particular therapeutic dosages. Yet curiously, in hyperbaric oxygen therapy, the concept of dosage is only rudimentary and there is no commonly agreed way to define the dosage. Moreover, there is no agreed way to evaluate the effects of this kind of therapy, and correspondingly no agreed way to correlate between the dose and the effect. The same may be said regarding other potential “energy-modulating” interventions into aging, whose definition is yet very nebulous. In certain studies, it was suggested to define the dose of hyperbaric oxygen therapy as the product of intra-barochamber pO2 (ATA), the duration of a single hyperbaric oxygenation exposure (hours), and the number of hyperbaric oxygenation treatments, yielding the dose unit: (ATA*h*N).[8,12] In those studies, the efficacy of hyperbaric oxygenation therapy was evaluated according to the number of patients who showed a significant clinical improvement in their neurological state in the course of the treatment (the percent of the total number of patients). The level of the therapy efficacy was compared with a corresponding value of the dose. For the treatment of acute ischemic stroke, a higher efficacy was indicated with increasing the average total hyperbaric oxygenation dose, reaching the maximum efficacy with the average doses of no less than 30 units (ATA*h*N).[12] However, such a definition of the dosages has not become consensus, and the definition of the therapy effects and of the dose-effect relations are rather vague and yet require a thorough elaboration and clarification. Hopefully, thanks to refinement of the definitions and massive additional data collection on dose-effect relations, including the evaluation of long-term effects and differential personalized effects in different patient groups (e.g. the elderly vs. the young) – oxygen therapy, hyperbaric oxygen therapy particularly, or “energy-modulating therapy” more generally – can become efficient means to alleviate aging-related conditions and increase healthy and productive life.

It is also necessary to note, that the obtained datasets of biomarkers, diagnostic parameters, and dose-effect relations, will be not only necessary for monitoring and personalizing treatment regimens, but will also be able to provide invaluable information for many yet unforeseen “quantified health” and “quantified longevity” applications – collecting a vast amount of health data on aging-related changes and their possible improvements to enable planning better informed therapeutic and life-style regimens and strategies to achieve healthy longevity.

Comprehensive physiological manipulation unit

Enhancing blood supply: The main purpose of oxygenation therapy (in particular hyperbaric oxygen therapy) is to directly enhance the supply of potentially deficient oxygen to the tissues that need it (while necessarily watching out against “burning out” and “oxygen toxicity”). However, oxygen supply can be improved by more indirect means, such as improving blood supply to the tissues. Historically, improved blood supply to the tissues (also for the purposes of rejuvenation) has been persistently sought. For example, the whole-body increase of the blood flow (hyperemia) has been achieved by various means ranging from hormone replacement therapy (by supplements, tissue transplants, and even operations on the endocrine organs) through diathermy (tissue heating), massage, exercise and baths.[1] The problems of oxygen delivery to the vital tissues have been also tackled from additional angles, such as oxygenated microparticles and “artificial blood”,[42] various forms of heart-lung machines, artificial hearts and other assisted circulation devices,[43] or pharmacological means to improve energy metabolism.[28] The blood flow can be also stimulated by electromagnetic devices.

As briefly mentioned above, recording electrodes and magnetic resonance devices may be employed for monitoring (for example during the course of oxygen therapy). Yet, in addition, stimulation electrodes may be also used for physiological manipulation purposes, in particular to stimulate nervous activity and blood flow, even to stimulate tissue regeneration, in particular blood vessels growth (angiogenesis – another potential means to improve tissue blood supply and oxygenation, but also requiring caution to avoid uncontrolled growth).[44] Such electromagnetic therapeutic devices have been sometimes termed “electroceuticals.”[45] They can be incorporated into the therapeutic regimens, either within the pressure chamber or as a part of accompanying regimens.

The incorporation or fitting of the additional therapeutic modalities within the pressure chamber can provide additional benefits. The ability provided by the pressure chamber to control and manipulate pressure, gas concentrations and temperature, can produce a convenient environment for physiological manipulation. Furthermore, with the addition of an infusion apparatus for delivering medications, including various regenerative and anti-aging medications (depending on the costs involved), this can become a multifunctional treatment unit. Some of its functions can be as follows.

“Resting state” induction: One possibility may be inducing a restorative “resting state” through a variety of physical means (pressure, temperature, oxygen and carbon dioxide concentration) as well as by electromagnetic and pharmacological means. Thus both reversible hypothermic and pharmacological resting states (reversible coma) are already becoming widely used clinical methods for recuperation and resuscitation, and can be incorporated into the chamber.[46] Just by using such physical manipulation means that are available in the pressure chamber – such as pressure, temperature, O2 and CO2 concentrations – a resting state can be induced insofar as rest and sleep are characterized by particular breathing and temperature patterns.[47] Temperature control can be another powerful means of physical manipulation. Thus, lower core body temperature has been correlated with longer lifespans.[48] In particular, lowering the body temperature (hypothermia) during hyperbaric oxygenation treatment could reduce energy (oxygen) demand by the organism and thus potentially lower oxygen toxicity. On the other hand, increased blood flow through heating may be used for therapeutic stimulation purposes. Within the chamber, temperature can be manipulated in both directions. The electric charge of the breathing mixture (e.g. negative ionization) can be also significant for recuperation vs. stimulation.[49]

Sleep enhancement: Sleep enhancement can be yet another promising restorative modality (in fact a form of “resting state”). In particular, slow-wave sleep (Stage 3, with synchronized EEG activity, showing slow waves with a frequency of less than 1 Hz) has been known to be vital for recuperation, presumably due to enhanced growth hormone production[50] or synchronization of physiological functions. [51] The restorative effects of sleep generally, and deep sleep in particular, may be also possibly due to activation of the immune response during sleep, or elimination of toxins, or other mechanisms.[52] This stage can be induced by a variety of methods, including: transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS),[53] other forms of sensory sleep stimulation[54] and a variety of slow-wave sleep enhancing drugs.[55] Sleeping in a hyperbaric chamber has already been practiced, and this combination of therapeutic modalities can be further explored and expanded if proven safe and effective.

All such technologies are yet extremely experimental, dose responses have not been thoroughly studied, hence side effects may be unpredictable. Both their short and long term effects are largely unknown, and the introduction of such additional technologies may become prohibitively expensive and unwieldy. They are mentioned here only as possibilities that can be further investigated and prospectively included within a potential “comprehensive restorative chamber” or “survival chamber.”

References and notes

[1] Ilia Stambler, A History of Life-Extensionism in the Twentieth Century, Longevity History, 2014, http://www.longevityhistory.com/.

[2] Ilia Stambler, “Human life extension: opportunities, challenges, and implications for public health policy,” in: Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 535-564, http://pubs.rsc.org/en/content/ebook/978-1-78262-435-6#!divbookcontent;

Alexander Vaiserman, Oleh Lushchak, “Anti-aging drugs: where are we and where are we going?” in: Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 3-10, http://pubs.rsc.org/en/content/ebook/978-1-78262-435-6#!divbookcontent.

[3]. Anthony Atala, “Extending life using tissue and organ replacement,” Current Aging Science, 1(2), 73-83, 2008, http://www.eurekaselect.com/95101/article;

Giuseppe Orlando, Shay Soker, Robert J. Stratta, Anthony Atala, “Will Regenerative Medicine Replace Transplantation?” Cold Spring Harbor Perspectives in Medicine, 3(8), a015693, 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721273/.

[4] Ronald Bellamy, Peter Safar, Samuel Tisherman, …, Harvey Zar, “Suspended animation for delayed resuscitation,” Critical Care Medicine, 24(2Suppl), S24-47, 1996, http://www.ncbi.nlm.nih.gov/pubmed/8608704.

[5] Yury P. Gerasimenko, Daniel C. Lu, Morteza Modaber, …, V. Reggie Edgerton, “Noninvasive Reactivation of Motor Descending Control after Paralysis,” Journal of Neurotrauma, 32(24), 1968-1980, 2015, http://online.liebertpub.com/doi/abs/10.1089/neu.2015.4008;

Max Schaldach, Electrotherapy of the Heart: Technical Aspects in Cardiac Pacing, Springer-Verlag, Berlin, 2012.

[6] Denham Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of Gerontology, 11, 298-300, 1956, http://www.uccs.edu/Documents/rmelamed/harman_1956_13332224.pdf;

Rajindar S. Sohal, “Role of oxidative stress and protein oxidation in the aging process,” Free Radical Biology and Medicine, 33(1), 37-44, 2002, http://www.sciencedirect.com/science/article/pii/S0891584902008560;

Rajindar S. Sohal, “Oxidative stress hypothesis of aging,” Free Radical Biology and Medicine, 33(5), 573-574, 2002, http://www.sciencedirect.com/science/article/pii/S0891584902008857;

Toren Finkel, Nikki J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, 408(6809), 239-247, 2000, https://www.nature.com/nature/journal/v408/n6809/full/408239a0.html.

[7] Gerald J. Gruman, A History of Ideas about the Prolongation of Life. The Evolution of Prolongevity Hypotheses to 1800, Transactions of the American Philosophical Society, Vol. 56 (9), Philadelphia, 1966.

[8] Gennady G. Rogatsky, Ilia Stambler, “Hyperbaric oxygenation for resuscitation and therapy of elderly patients with cerebral and cardio-respiratory dysfunction,” Frontiers In Bioscience (Scholar Edition), 9, 230-243, June 1, 2017, http://www.bioscience.org/2017/v9s/af/484/2.htm, https://www.bioscience.org/special-issue-details?editor_id=1746, https://www.ncbi.nlm.nih.gov/pubmed/28410116.

[9] The standard indications for the use of hyperbaric oxygenation, as established by the US-incorporated Undersea and Hyperbaric Medicine Society (UHMS), include: 1. Air or Gas Embolism, 2. Carbon Monoxide Poisoning, 3. Clostridial Myositis and Myonecrosis (Gas Gangrene), 4. Crush Injury, Compartment Syndrome and Other Acute Traumatic Ischemias, 5. Decompression Sickness, 6. Arterial Insufficiencies, 7. Severe Anemia, 8. Intracranial Abscess, 9. Necrotizing Soft Tissue Infections, 10. Osteomyelitis (Refractory), 11. Delayed Radiation Injury (Soft Tissue and Bony Necrosis), 12. Compromised Grafts and Flaps, 13. Acute Thermal Burn Injury; 14. Idiopathic Sudden Sensorineural Hearing Loss.

(Undersea and Hyperbaric Medicine Society (UHMS), “Indications for Hyperbaric Oxygen Therapy,” https://www.uhms.org/resources/hbo-indications.html.)

Yes, there is good evidence for the possible use of this treatment against other severe and chronic conditions. See for example:

Gennady G. Rogatsky, Avraham Mayevsky, “The life-saving effect of hyperbaric oxygenation during early-phase severe blunt chest injuries,” Undersea and Hyperbaric Medicine, 34(2), 75-81, 2007, http://archive.rubicon-foundation.org/xmlui/bitstream/handle/123456789/6468/17520858.pdf?sequence=1;

Ning Gu, Fumiko Nagatomo, Hidemi Fujino, Isao Takeda, Kinsuke Tsuda, Akihiko Ishihara, “Hyperbaric oxygen exposure improves blood glucose level and muscle oxidative capacity in rats with type 2 diabetes,” Diabetes Technology & Therapeutics, 12(2), 125-133, 2010, http://online.liebertpub.com/doi/abs/10.1089/dia.2009.0104;

Majid Kalani, Gun Jörneskog, Nazanin Naderi, Folke Lind, Kerstin Brismar, “Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers: Long-term follow-up,” Journal of Diabetes and its Complications, 16(2), 153-158, 2002, http://www.jdcjournal.com/article/S1056-8727(01)00182-9/fulltext .

Michael H. Bennett, Jan P. Lehm, Nigel Jepson, “Hyperbaric oxygen therapy for acute coronary syndrome,” Cochrane Database of Systematic Reviews, 2015(7), CD004818, 2015, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004818.pub4/full;

Peter Kranke, Michael H. Bennett, Marrissa Martyn-St James, Alexander Schnabel, Sebastian E. Debus, “Hyperbaric oxygen therapy for chronic wounds,” Cochrane Database of Systematic Reviews, 2015(6), CD004123, 2015, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004123.pub3/abstract;

Michael H Bennett, Barbara Trytko, Benjamin Jonker, “Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury,” Cochrane Database of Systematic Reviews, 2012(12), CD004609, 2012, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004609.pub2/abstract;

Richard A. Neubauer Research Institute, “Resources,” www.ranri.org/resources.html.

[10] Escobar S.J., Slade J.B., Hunt T.K., Cianci P., “Adjuvant hyperbaric oxygen therapy (HBO2) for treatment of necrotizing fasciitis reduces mortality and amputation rate,” Undersea and Hyperbaric Medicine, 32(6), 437–43, 2005, http://dspace.rubicon-foundation.org/xmlui/bitstream/handle/123456789/4061/16509286.pdf?sequence=1.

[11] Ingrid Moen, Linda E. B. Stuhr, “Hyperbaric oxygen therapy and cancer – a review,” Targeted Oncology, 7, 233–242, 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510426/.

[12] Gennady G. Rogatsky, Edward G. Shifrin, Avraham Mayevsky, “Optimal dosing as a necessary condition for the efficacy of hyperbaric oxygen therapy in acute ischemic stroke: a critical review,” Neurological Research, 25(1), 95-98, 2003, http://www.tandfonline.com/doi/abs/10.1179/016164103101201003; Optimal_dosing_as_a_necessary_condition_for_the_efficacy_

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James K. Walsh, Ellen Snyder, Janine Hall, Angela C. Randazzo, Kara Griffin, John Groeger, Rhody Eisenstein, Stephen D. Feren, Pam Dickey, Paula K. Schweitzer, “Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction,” Sleep, 31(5): 659–672 2008, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398757/.

Ilia Stambler

The discourse for the promotion of active and healthy longevity is expanding globally. Hopefully, the language of extending active and healthy longevity will become the common language around the world, in English and other national languages. It may help to recognize some key terms and concepts in this language. Below is an attempt to produce a short lexicon of some of the currently popular terms in longevity promotion. This short lexicon is of course very incomplete and is a work in progress. The readers are welcome to advise on improvements. See also: https://hpluspedia.org/wiki/Category:Life_extensionism

Active and healthy longevity (extending healthspan)

Increasing the average and maximal lifespan, accompanied by a reduction of morbidity. Synonym – extending healthspan (the healthy lifespan). The healthspan extension of the population is associated with increasing their activity and productivity and facilitates the development of all branches of economy. The advancement of active and healthy longevity requires the deployment of new approaches to health care management, such as precision medicine, early diagnosis, personalized and preventive therapy.

Biobanking

Procedures and services provided by biobanks, such as: collection, processing, storing, licensing and distribution of biological materials (cells, fluids, tissues) for their future therapeutic use, in particular in pharmacological research and regenerative medicine.

Bioinformatics

The application of methods of information processing for the solution of biological and medical problems and tasks, such as establishing diagnosis or selecting a treatment. Such tasks commonly require complex analysis of massive biological and medical data of various kinds (big data or multi-omics analysis) in order to obtain a comprehensive picture of biological processes, predicting the course of disease and evaluating the results of treatment. Bioinformatic analysis uses various methods of mathematical and computer modeling (including visualization and virtual simulation), biostatistics and information theory, artificial intelligence.

Biomarker of aging

Biological or physiological indicator of the aging process, allowing to describe and predict the process of aging and aging-related diseases, and the results of therapeutic interventions into these processes.

Cell therapy

Therapeutic use of cells and cell products to induce regeneration, improve function and other therapeutic effects.

Clinical trials

Experiments or observations done in clinical research on human subjects, to clarify the accuracy of diagnostic techniques, or benefits vs. risks of potential therapeutic interventions (such as drugs, medical devices or dietary supplements), establishing their efficacy and safety. Clinical trials in humans take place after extensive preclinical research establishing the feasibility of application and ethical committee approval establishing the desirability of testing in human subjects.

Epigenetic modulation

Induction of changes in gene function without changes in DNA sequence, including therapeutic and rejuvenating effects on cells and tissues. Examples of epigenetic modulators are methylation, small interfering RNAs, micro-nutrients.

Gene therapy

Therapy modifying the genetic information, with a change of DNA sequence, by activating or suppressing certain genes to achieve therapeutic effects, for example the production of proteins necessary for the organism, or elimination of pathogenic proteins. The modification of genetic information is often done by introduction into the organism of vectors-carriers of genetic information, such as retro-viruses or plasmids.

Geroprotecotrs (anti-aging medications)

Medications slowing down, stopping or potentially reversing aging processes, and as a result providing general prevention for aging-related diseases, such as dementia, cardio-vascular diseases, cancer, type 2 diabetes, obstructive lung diseases, etc. Potential geroprotective (anti-aging) substances under research and development include: anti-glycemic, hormone-modulating, mitochondria-modulating, immuno-modulating, probiotic, detoxifying and bio-regulating medications.

Induced Pluripotent Stem Cells (iPSCs)

The type of stem cells that could be produced (reprogrammed) from adult differentiated cells, using special chemical and biological factors (such as the Yamanaka factors), for further use in regenerative medicine. The main advantage of using such cells is the potential avoidance of immune rejection and solution of ethical problems, by using the patient’s own cells and tissues.

Monitoring

Observing the state of the organism, using various diagnostic technologies – either periodical or continuous, either mobile or stationary, either invasive or non-invasive. For example, monitoring technologies include such methods as ultrasound, magnetic resonance imaging (MRI), measurements of blood pressure, heart rate, gas exchange, EEG, ECG, etc. Data from monitoring are often collected in centralized databases (such as electronic medical records – EMR of the health system), or decentralized personal databases (in particular in different “quantified health” applications). The data from monitoring serve to prevent dangerous conditions and to improve therapeutic regimens based on individual patients data.

Multi-omics analysis

Combined analysis of information about the human organism, aimed to diagnose its condition and analyze the efficacy of specific types of treatment. The information is collected in a systemic way from different levels of biological organization (“omes”), including: genome – genetic information, as presented by DNA sequence; epigenome – the epigenetic markers of gene regulation; transcriptome – the collection of mRNA participating in the transcription of genetic information into proteins; proteome – information on the proteins present in the organism, or in specific cells or tissues; metabolome – information on products of the organism’s metabolism (metabolites); physiome – information on the physiological, such as energetic, parameters of the organism, etc. The information from the various levels (“omes”) is correlated with each other and with the clinical history (anamnesis) and therapeutic regimen to provide systemic, multi-faceted diagnosis and therapy.

Phases of clinical trials

Clinical trials, aimed to establish the treatment efficacy and safety in humans, proceed through several stages of phases: The preclinical stage: Testing the treatment (e.g. drug) in non-human models, e.g. in vitro testing (“in glass”) and in vivo testing (in model animals). After the preclinical experiments, ethical committee establishes the possibility and desirability of proceeding toward actual clinical trials in humans (Phases 0-4).

Phase 0 – Pharmacokinetics, particularly bioavailability and half-life of the drug (usually involving several human test subjects); Phase I – Testing of the drug on healthy volunteers or patients for dose-ranging and initial safety (usually tens of subjects); Phase II – Testing of the drug on patients to assess efficacy and side effects (usually a few hundreds of subjects); Phase III -Testing of the drug on patients to assess efficacy and adverse reactions (up to thousands of subjects); Phase IV – Postmarketing surveillance, i.e. observing the results of the drug use in the public, after its sales.

Precision medicine

An approach to disease prevention and treatment that takes into account precise individual differences in people’s biology and physiology, including genetics, environments and lifestyles, thereby giving the greatest chances of therapy success for the individual patients or specific groups of patients. This involves: Precise diagnosis – using extensive patients data to provide reliable and early indications of diseases and predict the response to treatments; Precise treatment – delivering treatments for individual patients and groups of patients that are most justified and effective for them, with the fewest side effects; Precise outcomes – thorough evaluation of the impact of the treatments on patients.

“4P” Medicine – Predictive, Preventive, Personalized and Participatory

Precision medicine is often associated with “4P Medicine” – i.e. medicine which is: Predictive (providing early preclinical indications of diseases), preventive (aimed for early prevention of diseases, before they take hardly manageable and costly forms), personalized (designed for specific patients, in accordance with their biology and environment) and participatory (empowering the individuals to take part in their physical evaluation and health management, under the expert supervision of the physician).

Regenerative medicine

A branch of translational medicine, including tissue engineering, cell therapy and molecular biology, which develops the processes of replacing, producing or regenerating human cells, tissues or organs, in order to restore or establish normal function of the organism.

Small molecules, biologics, nano-medicine

Substances with therapeutic properties, acting on various biochemical and molecular-genetic processes of the organism. Biologics – proteins and other biological molecules, used for therapeutic purposes (for example, vaccines or bio-regulators). Small molecules – chemical compounds, usually up to 100 nanometeres (1 nanometer = 1/1 bln meter). Nanomedicine – the use of nanoparticles and more complex nano-structures and nano-devices for diagnostic and therapeutic purposes (size up to several hundred nanometers).

Stem Cells (SC)

Non-differentiated cells, capable to differentiate into different types of specialized cells and tissues (e.g. muscle or nervous tissues). Stem cells are studied to be potentially used for regeneration or restoration of function of aging and diseased tissues and organs.

Testing – in vivo, in vitro, in situ, in silico

Conducting experiments on biological models, for example with the purpose of clarifying potential efficacy and safety of new medicines. The testing is possible: in vivo (in the living organism, e.g. in model animals), in vitro (“in glass” or “in a test tube”, i.e. outside the living organism, including “lab-on-a-chip” approaches), in situ (in the original condition or place, e.g. in the true conditions and place of a biological process), or in silico (using computer modeling of the behavior of experimental systems).

Tissue engineering

The application of a combination of cells, engineering and materials technologies, with suitable biochemical and physicochemical factors, to grow tissues for replacement or reconstruction, or to develop and test new pharmacological therapies. Examples of bioengineering systems include: bio-scaffolds, bio-reactors, 3D bio-printing, or tissue self-organization.

Translation (in medicine)

The process of translating scientific research to its application in clinical practice, including all the stages of research and development: from studies on cells and tissues, through animal studies and human trials, up to marketing, production and distribution. Methods are sought for the facilitation and optimization of this process.

Some potential interventions to ameliorate degenerative aging

By Ilia Stambler, PhD

The interventions into the degenerative aging process are still in their infancy. A long effortful road will yet need to be traveled from basic research on cell cultures and animal models to effective, safe and widely available human therapies. And many dangers to human health (such as overdose and overstimulation) and many unsubstantiated false claims yet await on this road that need to be guarded against as much as possible. Yet vast promising research is progressing, especially as regards potential pharmaceutical interventions into the aging process.[1] [2] [3] Below are some examples.

1. On November 28, 2015, the FDA approved the testing of Metformin, a decades-old anti-diabetic (blood sugar reducing) medication, as the first drug to treat degenerative aging, rather than particular diseases, due to its capacity to reduce cancers and other morbidities.[4]

2. On November 25, 2015, the FDA approved an adjuvant therapy (developed by Novartis) for a flu vaccine to boost immune response in older persons. This development goes beyond “a drug against a disease” model, but seeks an appropriate regulatory framework to support the underlying health of older persons, using “adjuvant” (i.e. “supportive/additional”) therapy.[5]

3. The immunosuppressant drug Rapamycin, believed to mimic the healthspan extending effects of calorie restriction (CR-mimetic), has produced improvements of energy metabolism, and to extend lifespan and delay aging in mice, and was also effective against particular aging-related diseases, such as Alzheimer’s disease, in human studies. Further research is done on Rapamycin’s analogs – the so called “rapalogs”, potentially with less side effects.[6]

4. By splicing the circulatory systems of animals (mice) together, via the process of “parabiosis”, young blood was shown to have rejuvenating effects on old tissues, including the heart, brain, and muscle tissues, with improved strength and cognitive ability. Some of the implicated rejuvenating substances included: Notch signaling activators, deactivation of the transforming growth factor (TGF)-β that blocks cell division, oxytocin, and Growth Differentiation Factor 11 (GDF11). In September 2014, a clinical trial by Alkahest in Menlo Park, California, became the first to start testing the benefits of young blood and young plasma in older people with Alzheimer’s disease.[7]

5. A new class of drugs – the “senolytics” capable of eliminating senescent cells and the accompanying pathologies – are being developed, in Mayo Clinic, Rochester, Minnesota and elsewhere.[8] Thus the combinations of the “senolytic” drugs Dasatinib and Quercetin proved effective against senescent human cells and in a mouse model. Together these drugs were able to reduce senescent cell burden, extend healthspan and improve physical exercise capacity in old mice, reducing their osteoporosis and other age-related pathologies.[9] Senescent cells can also be eliminated by immunological means, such as vaccines, antibodies and killer T cells.[10]

6. Resveratrol, a natural polyphenolic compound, among other sources found in red wine, has demonstrated the ability to up-regulate Sirtuin 1 (SIRT1) – an acknowledged prolongevity enzyme[11] important for enhanced stress response, cardiovascular protection, improved cognitive function and synaptic plasticity, and suppressing inflammation.[12] SIRT1 expression is generally related to the levels of energy metabolism, as indicated by NAD/NADH levels, which have also become targets for diverse pharmaceutical interventions (NAD replacement therapy).[13]

7. Dichloroacetate and bicarbonate represent a class of compounds and therapies that may have systemic effects on tissue redox and pH state, with broad implications for the aging process and derivative pathologies, such as cancer.[14]

8. Generally, regenerative medicine, using stem cells of various origins to rebuild, “regenerate” or improve the function of worn out and aging organs and tissues, can be promising for combating the degenerative pathologies of aging.[15] Even entire “replacement organs and tissues” can be grown outside of the body – using such methods as growing tissues on biodegradable scaffolds, 3D tissue printing, bioreactors or self-organization — to “replace” the worn out and aging body parts.[16] Yet, very recently a very promising direction in regenerative medicine has emerged – the induction of regeneration within the body by pharmacological means (e.g. using inhibitors of prostaglandin breakdown thus promoting cell proliferation).[17]

9. Of special importance for regenerative medicine against aging-related degeneration is the ability to regenerate the thymus gland (that produces the immune T-cells that play the crucial role for the immune defense). This importance derives from the fact that such an ability could dramatically improve therapy not only for aging-related non-communicable chronic diseases (such as heart disease and neurodegenerative diseases that are strongly related to altered immune response), but also help combat infectious, communicable diseases (like AIDS, Herpes and Influenza) thanks to improved immunity. Such regenerative ability for the thymus was shown by genetic engineering interventions (e.g. using over-expression of the FOXO gene)[18] and even pharmaceutical treatments (e.g.  using the FGF21 hormone).[19]

10. The extension of the telomere end points of the chromosomes, thus increasing the number of cell replications, by such means as genetically engineered overexpression of the telomere-repairing enzyme – telomerase, and even by some pharmacological stimulators of telomerase activity, have been associated with increased lifespan and reduced pathology in animal models.[20] [21] [22]

11. There have been many methods investigated for improving mitochondrial function and cellular respiration. Thus anti-oxidant molecules attached to positively charged ions (cations) have been targeted into mitochondria to eliminate oxidative damage at its origin (the SkQ ions).[23] In another approach, chemical compounds (in particular suppressors of the IIIQsite of the respiratory chain in the mitochondria) have been identified that can block the production of certain free radicals in cells without changing the energy metabolism of these cells.[24] A large additional array of boosters of mitochondrial activity and cellular respiration has been proposed, e.g. methylene blue, the naphthoquinone drug β-lapachone, supplementation with various components of the respiratory oxidative phoshorylation system – such as CoQ10, pyruvate, succinate, vitamins C and K, quercetin, various other anti-acidic, anti-toxic, and anti-oxidant substances.[25]

12. Anti-inflammatory medications have been widely tested to diminish aging-related degenerative pathologies, such as neuro-degenerative pathologies, and to extend healthy lifespan in animal models.[26] But also pro-inflammatory effects have been shown to be important for tissue regeneration.[27]

13. Diverse means are being developed to dissolve macro-molecular (cross-linked) aggregates that “clog” cell machinery. Some approaches include stimulation of cell autophagy that can help remove such aggregates (e.g. by introducing Beclin protein). Various “AGE-breakers” are being developed. These are, as a rule, small molecules capable of breaking “Advanced Glycation Endproducts” (AGE) that are chiefly responsible for the formation of macromolecular aggregates (e.g. glucosepane, one of the most common forms of cross-linked AGE products in collagen). Some of the therapeutic means against cross-linked aggregates include chelators (removing the metal ions that are important for the formation of the cross-links), enzymatic clearance (oxidoreductive depolymerization of the aggregates by enzymes), immunoclearance (using immune mechanisms, e.g. antibodies, to remove the aggregates), etc.[28] Yet, it needs to be noted that macromolecular aggregates, in certain amounts and under certain circumstances, may have a necessary function in the body too.[29] Removing too much of them and in wrong places may do more damage than good.

14. Keeping the body chemistry in balance is hoped to be achieved by supplementing deficient elements in the diet (e.g. vitamins, microelements, other essential nutrients), while eliminating excessive and therefore toxic elements (by such means as chelators, enterosorbents, dietary restriction, enhanced elimination).[30] But what is “the balance”? How much is “too much” or “too little”? The guiding rule is always “The dose makes the poison”.[3] Dietary interventions, that are being tested, include dietary restrictions of various kinds (mainly protein restriction and calorie restriction) that have been associated with extended lifespan in animal models and some health benefits in humans.[31] Also new ways are being sought to enrich the “microbiome” (intestinal bacteria populations) for healthy longevity[32], for example using probiotic diets – the idea that goes back to the origins of scientific aging research, over a century ago.[33]

15. Epigenetics (acquired or heritable changes in gene function without changes in DNA sequence), has been increasingly investigated and manipulated for its effects on aging and aging-related diseases, and their amelioration, at the level of the entire organism as well as particular tissues, for example, using demethylating agents, small interfereing RNAs (siRNAs) and micronutrients as potential therapeutic agents.[34]

16. Interventions into degenerative aging are now beginning to reach the “nano” level. Some of the uses of nanomedicine against degenerative aging include nanoparticles, such as Buckminsterfullerene or “bucky-balls” C60 with assumed antiviral, antioxidant, anti-amyloid, immune stimulating and other therapeutic activities, and some reported lifespan extending results in animal models.[35] Moreover, there even have been announced the first operating medical nanorobots, mainly intended to assist in precise drug delivery, acting as prototypes of artificial immune cells.[36] [37] These nanodevices were mainly intended to eliminate cancer cells, but could also be used to eliminate other types of cells, e.g. senescent cells. In another area of development, oxygenated micro-particles seem to be very promising for life extension, especially in critical conditions, as oxygen deprivation is the main (or even the ultimate) cause of death.[38]

17. Anti-aging and life-extending interventions do not necessarily need to be chemical or biological, but can also be physical, in particular as relates to various resuscitation technologies (hypothermia and suspended animation,[39] oxygenation,[40] electromagnetic stimulation[41]). Such technologies represent probably the most veritable means for life extension, demonstrably saving people from an almost certain death. But similar principles could perhaps be used for more preventive treatments and in less acute cases.

18. It seems to be impossible to speak of “treating” or “curing degenerative aging” without the ability to diagnose this condition and to reliably assess the effectiveness of interventions against it.[42] Hence a wide array of biomarkers and clinical end points are being sought to diagnose degenerative aging and aging-related ill health, and to determine correct “biological age”.[43] Clinically applicable and scientifically grounded diagnostic criteria and definitions for aging may also have profound encouraging implications for the regulation and promotion of research, development, application and distribution of anti-aging and life-extending and healthspan-extending  therapies.[44] [45]

Aknowldgedment

I thank Steve Hill and Kevin Perrott for their suggestions regarding the diverse research areas. Any additional suggestions are appreciated.

References

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A History of Life-Extensionism in the Twentieth Century

By Ilia Stambler, PhD

A book on the history of Aging and Life Extension research, freely available online at:

http://www.longevityhistory.com/

And as a hard copy at:

http://www.amazon.com/History-Life-Extensionism-Twentieth-Century/dp/1500818577/

Proceedings from the sales of this book will be donated to international longevity research and advocacy projects, such as Israeli Longevity Alliance http://www.bioaging.org.il/ , Longevity for All http://www.longevityforall.org/ and others, or used to distribute more free copies to centers of learning around the world to increase education on aging and longevity research http://www.longecity.org/forum/topic/75826-donation-of-books-on-life-extension-to-university-libraries/

You can find more information on the subject at:

http://www.longevityhistory.com/ and  https://www.facebook.com/LongevityHistory

Thank you for your interest and feedback!

The book Summary:

This work explores the history of life-extensionism in the 20th century. The term life-extensionism is meant to describe an ideological system professing that radical life extension (far beyond the present life expectancy) is desirable on ethical grounds and is possible to achieve through conscious scientific efforts.

This work examines major lines of life-extensionist thought, in chronological order, over the course of the 20th century, while focusing on central seminal works representative of each trend and period, by such authors as Elie Metchnikoff, Bernard Shaw, Alexis Carrel, Alexander Bogomolets and others. Their works are considered in their social and intellectual context, as parts of a larger contemporary social and ideological discourse, associated with major political upheavals and social and economic patterns.

The following national contexts are considered: France (Chapter One), Germany, Austria, Romania and Switzerland (Chapter Two), Russia (Chapter Three), the US and UK (Chapter Four).

This work pursues three major aims.

The first is to attempt to identify and trace throughout the century several generic biomedical methods whose development or applications were associated with radical hopes for life-extension. Beyond mere hopefulness, this work argues, the desire to radically prolong human life often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery. It will be shown that novel fields of biomedical science often had their origin in far-reaching pursuits of radical life extension. The dynamic dichotomy between reductionist and holistic methods will be emphasized.

The second goal is to investigate the ideological and socio-economic backgrounds of the proponents of radical life extension, in order to determine how ideology and economic conditions motivated the life-extensionists and how it affected the science they pursued. For that purpose, the biographies and key writings of several prominent longevity advocates are studied. Their specific ideological premises (attitudes toward religion and progress, pessimism or optimism regarding human perfectibility, and ethical imperatives) as well as their socioeconomic conditions (the ability to conduct and disseminate research in a specific social or economic milieu) are examined in an attempt to find out what conditions have encouraged or discouraged life-extensionist thought. This research argues for the inherent adjustability of life-extensionism, as a particular form of scientific enterprise, to particular prevalent state ideologies.

The third, more general, aim is to collect a broad register of life-extensionist works, and, based on that register, to establish common traits and goals definitive of life-extensionism, such as valuation of life and constancy, despite all the diversity of methods and ideologies professed. This work will contribute to the understanding of extreme expectations associated with biomedical progress that have been scarcely investigated by biomedical history.