Michael Fossel, MD, PhD – Written evidence (INQ0009)

Extending the Health Span

The cause of aging is ignored by the medical establishment who, ironically, argue that aging is the greatest risk factor for disease.

-- Leonard Hayflick, 2019

Personal Communication

1. The Problem: Extension of a healthy lifespan with minimal age-related disease is both socially desirable and clinically feasible. It is socially desirable because it decreases human suffering and thereby reflects the compassion necessary to a healthy society, as well as lowering the current – and projected increases in the – financial burden caused by age-related disease. Clinical feasibility, however, rests precisely upon a valid and fundamental understanding of the aging process itself. To date, there are no clinical interventions that alter either aging or the underlying pathology of age-related disease. These two facets – aging and age-related disease – are linked: effective interventions in age-related disease require that we understand aging.

2. While we have numerous clinical interventions targeting age-related disease, none of these interventions alter the underlying disease process. Currently, we treat symptoms and biomarkers rather than the fundamental pathology per se. Although we can, in some cases, reduce mortality and morbidity, we do not affect the aging process that drives such diseases. This is most poignantly seen in the case of Alzheimer’s disease, a disease that is fatal and has no effective clinical intervention. The global medical consensus is that there is no currently available therapy that changes either the vector or the final outcome of the disease. To date, billions of pounds (by pharmaceutical and biotechnology firms as well as by governmental agencies) have been wasted to no measurable effect, as assessed by the clinical outcome for patients with Alzheimer’s disease.

3. Our ability to intervene in other age-related diseases share parallel issues. We can, for example, affect the mortality and morbidity of age-related vascular disease (e.g., with diet changes, smoking cessation, control of blood pressure, the use of statins, etc.), but we have no available interventions that can either reverse or stop the underlying pathology within the vascular endothelial cells play the primary role in such pathology. In regard to age-related vascular disease, as well as osteoarthritis, osteoporosis, and age-related renal failure, we may slow but are unable to stop or reverse age-related disease. We treat symptoms, not causes.

4. The lack of progress in treating age-related disease has been due to the lack of any consistent, systems model of aging. Such a model should: a) account for the current failure to effectively treat age-related disease, b) offer a comprehensive explanation for all age-related human (and animal) disease, c) identify an effective point of intervention to prevent and cure age-related disease, as well as extend the healthy lifespan.

5. The Cell Senescence Model: Advances over the past two decades have resulted in a model – the cell senescence model of age-related disease – that answers the above questions, is technically feasible in clinical trials, and is supported by all current data. Moreover, it has solid predictive validity, precisely accounting for failed clinical trials in diseases such as Alzheimer’s (where monoclonal antibodies were unsuccessfully used to target beta amyloid, for example) and accounting equally well for the successful animal trials in which cell aging has been reset with good clinical results.

6. The predictive validity of the new model accounts for all previous clinical trials data, specifically those trials aimed at Alzheimer’s disease. This model predicted that any interventions aimed at beta amyloid or tau tangles would face three obstacles: 1) these targets are not causal, but lie downstream in the cascade of pathology, 2) they are only a single pathological process among dozens of such downstream processes, and 3) their turnover is a dynamic process that cannot be effectively treated by small molecular interventions. To date, all such attempted clinical interventions (such as the use of monoclonal antibodies, BACE inhibitors, etc.) have resulted in, at most, transient slowing in the disease process. The cell senescence model predicts that interventions aimed at a single part of the pathology (i.e., beta amyloid plaques) will show small and transient delays in the disease process, but no affect on the subsequent vector of such a process and no change in final mortality rate. All clinical trial results, in Alzheimer’s and other age-related diseases, have been consistent with the cell senescence model.

7. The cell senescence model accounts for both human and animal age-related disease, offering a comprehensive, systems model that accounts for known pathology. The model suggests that aging occurs when somatic cells alter their pattern of gene expression and are no longer capable of appropriate cell maintenance. Such changes have subtle but pervasive negative consequences for DNA repair, mitochondrial energy maintenance, molecular replacement, membrane maintenance, and other aspects of cell function. The increasing cell dysfunction results in secondary tissue dysfunction and is manifested clinically in age-related disease. The model can be summarized as follows: a) aging and age-related diseases are the result of cellular aging, b) cellular aging is manifested by widespread changes in gene expression, and c) the changes in gene expression are modulated by changes in telomere lengths.

8. The age-related changes in gene expression result in slower turnover in any pool of molecules, such as beta amyloid, mitochondrial enzymes, lipids, DNA repair enzymes, and hundreds of other biologically active molecules. In aging cells, the slower rate of molecular turnover results in a gradual increase in the accrual of overall damage in such pools of molecules. Cellular aging drives the age-related increase in molecular damage, the loss of cell function, and the clinical progression of disease. Cell senescence results in age-related damage, not the other way around.

9. Changes in gene expression (epigenetic changes) are central to age-related disease and define cell aging. Different individuals (with slightly different alleles and with slightly different epigenetic baselines) can be expected to have different disease outcomes. While all human patients share the same fundamental mechanism of cell aging, the specific clinical outcomes depend upon small but significant genetic and epigenetic differences between individuals. One patient will be prone to age-related vascular disease (e.g., myocardial infarction, aneurysm, stroke, etc.), while another will be prone to early-onset age-related CNS disease (e.g., Alzheimer’s, Parkinson’s, etc.)

10. Although the overall outcome of cell senescence – an increasing risk of age-related disease and dysfunction – is shared between and within species, individual outcomes will vary with the genetic and epigenetic backgrounds. This variance has caused frustration in going from animal studies to human trials, but the shared fundamental mechanisms (e.g., cell senescence and epigenetic shifts) offer a novel and viable point of intervention.

11. While cell senescence – and hence age-related clinical disease – largely correlates with chronologic age, variability in aging and age-related disease results from a wide number of upstream variables that can accelerate cell senescence and disease (see figure).

12. For example, infection, trauma, or radiation can accelerate cell senescence. A large number of variables can increase the rate of cell aging including genes[1],[2],[3],[4], chemotherapy[5],[6], toxins[7],[8],[9], trauma[10],[11],[12], hypertension[13],[14], stroke[15], hyperglycemia[16],[17], microbiome[18], stress[19],[20], hormones[21],[22],[23], infection[24],[25], senolytic therapy[26],[27], etc. Despite these upstream variables, the changes in epigenetic expression are a shared mechanism and this common mechanism provides a unique therapeutic opportunity.

13. Effective Intervention: Cell senescence was first described more than 50 years ago[28],[29], and its implications for age-related disease were outlined in both the lay[30] and medical literature more than 20 years ago[31],[32] and repeatedly implicated since[33]. Cell senescence was first shown to correlate with[34],[35],[36], then to be the causal outcome of telomere shortening and amenable to resetting in vitro.[37] Subsequently, resetting of telomere length was shown to reset function in aging human tissue in vitro,[38],[39],[40] further underlining cell senescence as a viable point of clinical intervention.[41] Oxford University Press published a comprehensive textbook describing this model in detail, as well as offering potential points of clinical intervention.[42] Recent studies, articles, and books have reviewed and supported the potential value of this model as an effective point of intervention in age-related disease[43],[44],[45],[46],[47].

14. Critically, such changes in gene expression have been successfully reset in human cells, human tissues, and laboratory animals, and are now feasible in human clinical trials. In the case of Alzheimer’s disease, for example, cell aging in both glial cells and vascular endothelial cells result age-related disease. Interventions to reset cell aging, though the use of telomerase (which relengthens telomeres and resets gene expression), are protective[48] and can reverse age-related changes in mice, including improvement in brain volume, neural stem cell function, and age-related behavioral changes.[49],[50]

15. The cell senescence model offers a novel point of intervention for human clinical trials which should prove uniquely effective and has no clinical precedent. It requires a one-time dose of a viral vector that delivers a normal human gene (hTERT) which is transiently expressed and which resets gene expression to the pattern typical of normal, young, non-diseased cells. Initial human trials (e.g., phases 1-3) will target Alzheimer’s disease and are budgeted at far less cost (£ 8.5m) than those typical of large global pharmaceutical trials, as well as requiring both fewer patients (one dozen) and a shorter trial (6 months) to demonstrate efficacy in reversing symptoms. Of equal importance, the projected per capita treatment cost after the initial human trials is estimated to be substantially less than the annual per patient cost of Alzheimer’s (approximately £32k). The approach can be demonstrated at low cost and within a short time period, while enabling lower future healthcare costs and more manageable budgeting, while preventing and curing Alzheimer’s and other age-related diseases.

16. Completion of human testing can be accomplished at any NHS site that has access to CNS imaging modalities, routine laboratory tests, and behavioral testing for Alzheimer’s patients. An initial human trial will treat twelve patients with moderately severe Alzheimer’s disease for six-months at a cost £ 8.5m for the phase 1 trial.

17. Implications: The policy implications of such therapy are ubiquitous and unparalleled. The healthcare delivery system could effectively treat (potentially cure and prevent) age-related diseases and do so at a lower cost than either current or projected budgetary levels.

18. Without an effective intervention for age-related diseases, current projections suggest that healthcare will become unaffordable within this century, effectively bankrupting national healthcare systems such as the NHS. Historically, however, prior to the advent of the Salk polio vaccine, the same outcome was projected for the costs of treating polio, suggesting a bankrupt healthcare system by 2000 due to the costs of rehabilitation, nursing care, iron lungs, etc. In both cases – age-related disease now and polio in 1950 – such projections have been based upon the assumption that no fundamental change would occur to undercut and falsify such financial projections. With the advent of the Salk vaccine in 1954, earlier projections were proven baseless. For example, the current global costs of polio immunization average 10¢/patient, a tiny fraction of the current global (or any national) healthcare budget. The same reasoning pertains to our current concerns regarding healthcare budgets, and for the same reason, as we are able to demonstrate an effective intervention with historic implications for treating clinical disease.

19. If the above model of age-related disease is accurate and if implemented, then the costs of treating age-related disease will fall substantially, to perhaps 10% of current annual costs, rather than rising to fiscally unsustainable levels. The approach is clinically feasible and economically reasonable. Health span can be increased and will reduce funding needs both personally and nationally.

27 August 2019