To gauge the effectiveness of anti‐‐aging medical therapies, surrogate markers, or biomarkers, are used instead of the improvement of specific symptoms to evaluate outcome. Traditionally, when investigators want to measure endpoints within a short time frame, instead of waiting for more clinically important endpoints, surrogate markers are employed. Although anti‐‐aging medicine uses surrogate markers in part because experiments involving life span would be impractical in humans, this is not the primary reason for their use. Rather, surrogate markers are an important way to measure biological function: hence the portmanteau biomarker.
The need to redefine the term ‘biomarker’ is linked to the new primary objective of medicine: to optimize biological function while blocking the initiation of disease. In contrast, the traditional approach to medicine is interventional and designed to alter disease progression. Thus, this dichotomy stems from the point at which the therapy is aimed: maintaining health versus treatment of pathology.
The advent of the computer has made it feasible to simultaneously evaluate a large number of biomarkers while organizing them into distinct groups. This allows for a comprehensive estimation of the effectiveness of anti‐‐aging therapeutics and a more constructive use of nutraceuticals tailored to an individual. Over the last five years, we have developed a specialized computer program that simultaneously evaluates more than one hundred biomarkers grouped on four levels. With this tool, different aspects of the aging process can be compared and relationships between biological function and biomarkers clearly ascertained. A graphic analysis allows for pattern recognition, which helps the patient and practitioner clearly grasp relationships and decide on treatment therapies aimed at the organ, cellular, and molecular levels. As the future unwinds, more biomarkers will be validated, and the techniques available to measure them will expand. One of the most significant technologies is the microarray gene ‘chip.’ Using the same technology as silicon computer chips, the only exception in the construction of the gene ‘chip’ is that the DNA paths, representing the genes for electron travel, are embedded into the chip. Our software program will continue to evolve as new biomarkers emerge so that the effectiveness of anti‐‐aging therapies may be evaluated down to the most fundamental level.
The current software measures molecular and chemical changes in the body, likely resulting from changes in gene expression, after specific treatment therapies have been performed. The induction and silencing of various genes is extremely important during development and may play a causal role in the alterations of biomarkers associated with aging. Therefore, one of the goals in selecting a panel of biomarkers of aging should be to represent the age‐‐related changes in gene expression, which have recently been defined. The genetic alterations associated with the aging process may be influenced by a variety of factors that, until recently, would have been called epigenetic: micronutrients, diet, exercise and mind state.
At our clinics, present therapies center on changing the cellular milieu and therefore influencing gene expression. This is accomplished using a combination of various treatments, which may include pharmaceuticals, hormonal replacement therapy, micronutrient nutraceutical supplements, calorie and macronutrient ratio regulation, physical exercise regimens, mind//body exercises, and relaxation. The combination of therapies is chosen based on the patient's biomarkers, collected from a panel of physiologic tests; body composition measurements; histologic analysis; and assays of the blood, saliva, and urine. The goal of therapy is to optimize physiologic function and functional antioxidant status while balancing biomarker levels to achieve and//or maintain values prevalent in the second and third decades of life.
One of the difficulties with this approach is due to biological individuality: variation from person to person. In fact, because not every hormone varies consistently with age, determining normal and desirable values is not always straightforward. One approach is to establish a biomarker profile in early adulthood. This allows the practitioner to do more that make educated guesses based on elusive statistics about human beings. In addition, this approach makes it possible to identify altered metabolism as the culprit for declining biomarkers.
A salient example of this is the age‐‐related increase in the conversion of testosterone into metabolites, estradiol, and dihydrotestosterone in men. This is due to the increased expression of two genes: aromatase and 5‐‐alpha‐‐reductase. Although testosterone levels decline with age, there is no statistically significant increase in either of their metabolites when a large group of men are examined. This is because of a wide variation of these hormone levels of these hormone levels even at a young age. High levels of dihydrotestosterone, for example, are not necessarily undesirable unless they are the result of age‐‐related increases in the expression of 5‐‐alpha reductase; there is no increase in the risk of prostate cancer for men who are in the highest quartile of dihydrotestosterone levels throughout life. The reason the age‐‐related increase is detrimental is probably because of the fact that testosterone declines as metablism increases. In any event, the metabolism of these steroid hormones is easily modulated with plant‐‐derived substances.
In addition to the lab data, which documents altered gene expression, subjective improvement is also an important part of our program. The combination of objective and subjective observations, can validate the effectiveness of an anti‐‐aging program. Although scientists are partial to objective documentation, the subjective component is critical for the success of any preventive therapeutic program as compliance is the sine qua non.
One example is a graphic sample of our patented Biomarker Matrix Profile ((BMP)) is being used to evaluate anti‐‐aging therapeutics. This state‐‐of‐‐the‐‐art tool provides the most detailed picture of the effectiveness of anti‐‐aging treatments.
In the coming years a few seminal technologies will give rise to a more comprehensive BMP with many new uses. The nascent technologies that will drive this evolution are:
Gene chips
Genomics
Gene transfection
Stem cell therapy
Nanotechnology and artificial intelligence
With the rapid development of gene chips, gene expression easily will be measured in individuals. This gives doctors a more complete mechanistic picture of what happens in the body during the aging process. At present, molecular changes are routinely documented, however, doctors cannot discern whether these changes are at the level of gene expression or due to post‐‐translational factors. Gene chips will make it possible to define optimal gene expression with the imminent completion of the Human Genome Project, which will provide the code for life. While the ability to read the blueprints of an organism marks a major benchmark in the history of life, the simultaneous appearance of the computer and the gene chip will allow this information to have acute clinical relevance. Thus, the newly deciphered information within the 23 pairs of human chromosomes will be a primary force in the evolution of biomarkers, representing a new branch of science called genomics. The pattern recognition capacity of a computerized gene chip will be as significant an advance as the ability to define the basal gene expression pattern responsible for the healthy period of young adulthood.
Another example demonstrates how a gene chip works. These gene chips are composed of a selected sequence of human genes, which can be chosen to monitor the expression of key genetic sequences involved in the aging process. RNA is isolated from a subject's cells and tagged with a material that fluoresces when the RNA binds to its complementary DNA. A spectrophotometer scans the chip and a computer catalogues the fluorescent areas and thus identifies which genes are being expressed. This technology is easily adapted to determine the effects of anti‐‐aging therapies on gene expression over the short and long term. Furthermore, basic research on aging has already profiled the genes, which are altered during the aging process. These detrimental alterations do not occur during caloric‐‐restriction life span‐‐extension experiments in animals. The major families of these genes are involved in the regulation of glucose, modification of DNA, modulation of inflammatory processes, and the control of oxidation, among others. Measuring discrete alterations in gene expression will greatly enhance the sensitivity of the BMP.
In addition, to these improvements in the diagnostic capacity of the BMP, both DNA transfection and stem cell therapy will have a radical effect on efforts to slow the aging process. Currently, attempts are being made to transfer plasmid vectors containing DNA sequences or genes into a subject involving only the simplest genetic engineering technology. Although this work initially is being carried out only in the patients who are most ill, the techniques that are developed easily will be applied to healthy individuals for the purpose of optimizing biomarkers and managing the aging process. For example, in the immediate future, transfecting DNA into muscle cell, or possibly even directly injecting RNA via phospholipid encapsulation ((a transient alteration)) to help manage control of oxidation will be possible. Many studies support the observation that high levels of intrinsic anti‐‐oxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, are correlated with increased life span. Additional studies in animals demonstrated that striated muscle cells take up the genes coding these antioxidant enzymes and express functional enzymes. Thus, current technology makes therapies like this viable in principle. Focusing on the key intrinsic anti‐‐oxidant systems with DNA transplant technology would be one of the most straightforward ways to slow aging and limit free radical damage.
The engineering and cloning of stem cells is being intensely studied in many laboratories around the world. Experiments such as the cloning of ‘Dolly’ clearly point to the possibility of inserting differentiated adult DNA into enucleated stem cells once stem cell clones are available to regenerate any component of the human body. Stem cell therapy involves introducing a new population of cells in an embryological form, which do not trigger immune rejection because they are not differentiated enough to generate an antigenic response. As the techniques of molecular biology become more sophisticated, clones of cells with embryological characteristics will be produced from cells in the patient's body.
The use of stem cells should help to answer the hypothesis that mitochondria are key players in the aging process, an area of recent intense speculation. Stem cells introduce virgin mitochondria into an aging body, which help upregulate ATP production. Many experiments have indicated that the loss of mitochondrial repair and biosynthetic enzymes is a hallmark of aging. Mitochondria are crucial for maintaining the body in a state of negative entropy, meaning that mitochondria are responsible for maintaining organization.
It is through the enhanced cellular energetics that processes, such a cyclic AMP‐‐mediated cytokine amplification of hormonal signals is favored. This effect may extend from the transplanted cell populations to neighboring endogenous cells. With more advanced stem cell therapy we will also be able to selectively target key organ systems that have been impaired or destroyed during the aging process, and more specificallywe will be able to repair damage within key organ sites themselves. Based on what germ cell line is expanded or cloned, organ specific anti‐‐aging therapy will be possible.
An important area of research in the immediate future will be to focus upon the restoration of the central nervous system's neuronal function. This will probably be accomplished through intrathecal stem cell injections, probably of ectodermal origin, used to restore key brain centers responsible for glucose and cortisol regulation ((e.g., VML and//or DML nuclei of the hypothalamus)). Thus, by enhancing the regulation of blood glucose through tighter control of insulin, cortisol, and glucagon, important biomarkers of aging, such as glycation and inflammation will be more readily controlled and balanced as in a young adult. Furthermore, stem cell treatment for improved central nervous system function will provide treatment options for the most feared aspect of aging: mental deterioration and Alzheimer's disease. After all, longevity is of little use if it can't be enjoyed. ((Illustration 5 details the effect of Alzheimer's disease on the brain.))
A few years after these technologies become mainstream in anti‐‐aging therapies, the ultimate anti‐‐aging technology will be ready for clinical application: nanotechnology. ((See example Anatomy of a Nanoprobe.)) In its nascence, nanotechnology will be applied at the macroscopic level to treat anatomical defects, possibly surface damage to the skin. As it rapidly matures, this new technology will sharpen its resolution to focus on the cellular and molecular levels for applications such as DNA repair. ‘Biobots’ will be designed to repair and reconfigure DNA; thereby making it possible to reverse DNA damage and inherited genetic lesions. The application of these technologies will allow for optimal gene expression and repair of any inherited defects. With this ability, the medical community will be able to push the limits of optimal life span and health span to limits heretofore only imagined.
In summary, the following are the salient features of 20th century anti‐‐aging therapy:
Genetic sequence is unknown at the time of treatment.
Gene expression is unknown at the time of treatment.
Interventions range from pharmaceutical to nutraceutical.
Measuring a collection of biomarkers validates therapies.
Computers allow for pattern recognition.
This describes anti‐‐aging therapy as currently practiced at the Longevity Institute International using the patented BMP. In essence, we are documenting improvements in physiologic, cellular, and molecular function, which may be the result of improved gene expression. Altered gene expression cannot be directly documented without incorporating a gene chip into the profile. More importantly, the current arsenal of therapies attempts to optimize biological function without altering genetic content. Nonetheless, optimizing biomarkers makes it possible to document changes resulting in improved biological function.
Our panels of biomarkers, which include surrogate markers, have been correlated with positive effects on health span and quality of life. While extensions in human life span are impossible to prove at present, data from animal models have strongly implicated alterations in certain classes of genes in the suppression of age‐‐related disease.
The anti‐‐aging therapies of the near future, within the next 5–10 years, will undergo a dramatic transformation. The anti‐‐aging clinic of the future will read the patient's genetic sequences and measure gene expression by extracting small samples of DNA and RNA and comparing them against the optimum patterns generated by the human genome project. This will allow genetic defects to be detected and gene expression to be monitored. Anti‐‐aging therapeutics in the early part of the 21st century will combine the present therapeutic regimens with the new technologies of DNA transplants, stem cell therapy, and telomerase therapy.
Furthermore, these therapies will be directed at poor expression of specific genes and alterations in biomarkers. Ultimately, the therapeutic endpoints are increased health span, improved quality of life, and slower appearance of age‐‐related disease. With the use of the new technologies, we will be able to document the effectiveness of anti‐‐aging therapeutics on altered gene expression involved in aging.
The anti‐‐aging therapies of the more distant future, within the next 10–20 years, will involve direct manipulation of genetic sequences within live human beings. Again, starting with a sample of the patient's DNA and RNA, a more advanced and highly selective gene chip, the content and expression of the patient's nuclear and mitochondrial DNA, will be evaluated. Genomics, by then a mature science, will provide a more detailed analysis of inherited and acquired genetic defects. A vast array of genes will be analyzed, such as those involved in important processes like hormone production, signal transduction, signal amplification, genomic stability, oxidative phosphorylation, DNA repair, transcription, translation, protein turnover, etc.
This expanding universe of bioinformatics, gene manipulation, and nanotechnology will make it possible to identify defects, propose solutions, and carry them out using custom designed devices. These novel nano‐‐machines, which are designed to carry out intracellular repairs on defective genes, according to the information harvested from gene chips, easily will be administered in a doctor's office. A computerized biomarker profiler, incorporating gene chips, will document the results. This should make it feasible to markedly extend life span and health span, pushing the limitations and definitions of human capacity.
The ability to document changes in gene expression and repair of DNA sequences will transform therapeutics into a discipline which is custom tailored for each instance of disease. This technology, coupled with the logarithmic growth of computer intelligence, in some measures surpassing human IQ, and improvements in software programs, to mimic neural networks, will vastly increase our ability to understand complex relationships between systems. The 21st century will usher in a new era of medicine that finally treats the causes and not the effects of aging, right down to the genetic level. We will then be able to control our genetic “software” and thus, direct our prospective evolution. For the first time in the history of medicine, technologic innovation may no longer be the rate‐‐limiting step driving the discipline.