New Evidence of the Limits of Dominant Therapeutic Paradigms

Biomedical research has traditionally focused on identifying and correcting the abnormalities in metabolic pathways that lead to disease states. However, this approach suffers numerous side-effects due to the complexity of metabolism. It is also inappropriate to treating many age-related diseases, which arise as a result of damage accumulated over decades of normal function. Regenerative engineering, by focusing instead on the removal of this damage, largely avoids both of these chronic problems.
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At the core of SENS Foundation’s strategy to comprehensively cure the diseases and disabilities of aging is a new biomedical heuristic: regenerative engineering.(1-3) To date, the dominant therapeutic strategy for both specific age-related diseases and (to the extent that it has been contemplated) the degenerative biological aging process itself, has been based on altering metabolic pathways. Biomedical research has centered on  the detailed understanding of pathways seen to be contributing to disease etiology or pathogenesis, and the identification of  putatively dysfunctional components (hormones, receptors, enzymes, cytokines, etc), which are then targeted for manipulation by small molecules or other means in hopes of normalizing function and thereby alleviating symptoms or slowing progression of pathology. Atherosclerosis, for example, is treated by manipulating the HMG-CoA reductase pathway with statin drugs, reducing the production of LDL cholesterol  in order to slow the progress and increase the stability of atherosclerotic lesions. Similarly, clinicians manage blood pressure with a range of agents to reduce the risk of heart attack and stroke, and blood glucose levels with insulin, sulfonylurea derivatives, thiazolinediones, and other agents to decelerate the progress of diabetic complications.

To the extent that this strategy has been effective in risk reduction and management of some specific diseases, there is a critical flaw in the unconsciously-drawn analogy between its use in the development of therapies to manage specific diseases, and its potential for the treatment of the degenerative aging process. Unlike most non-communicative diseases, degenerative aging is not the result of the dysfunction of metabolic pathways, but of the the undesirable long-term side-effects of their normative biochemistry. Put another way: biological aging is the pathological result of perfectly-functioning, healthy – but necessarily imperfect – metabolic processes. Hence Dr. de Grey’s quip that “aging is a side-effect of being alive:” carrying out the normal processes underlying life itself entails the generation of aging damage, and its gradual accumulation in cells and tissues over time leads to their progressive age-related dysfunction.

Thus, transposing the conventional drug-development pathway onto the aging process necessarily entails interfering with the normal metabolism – and doing on an indefinite basis, from the day that a “patient” first begins therapy until his or her death. But of course, those same pathways evolved to ensure survival and fitness, and their existence and the normal mode of regulation are the very basis of  ordinary health and function. We interfere with the intrinsic operation of such pathways at our peril.

It was the recognition of this fundamental weakness in the dominant therapeutic strategy for age-related degeneration that led to the advancement of regenerative engineering as an alternative heuristic as an alternative. This new heuristic is based on allowing metabolism to carry on under its intrinsic regulatory regime, while severing the link between them and later, downstream pathology by directly removing, repairing, replacing, or rendering harmless the inert damage of aging that renders biomolecules, cells, and tissues progressively dysfunctional, and results in age-related progression in  disease, disability, dependence, dementia, and ultimately death.

Approaching the Limits of the Old Paradigm

But recent studies highlight the dangers of perturbing even the abnormal function of metabolic targets involved in ongoing disease states. The increased risk of adverse cardiovascular events associated with rofecoxib (Vioxx) and possibly other cyclooxygenase-2 inhibitors as compared with other non-steroidal antiinflammatory agenats result from the unpredicted effects of inhibiting their primary and putatively more metabolically dispensable inducible target. Combination therapy with a statin and Pfizer’s first-of-class CETP-inhibitor torcetrapib dose-dependently increases HDL-C levels by 50–100%, while reducing LDL-C by ~15% beyond the effect of atorvastatin alone, but not only fails to affect the progression of atherosclerotic lesions, but  increases the rate of cardiovascular events and mortality. Many, including the advocates of rival CETP inhibitor drugs still in development, argue that the cardiovascular risk may have been due to off-target effects on the aldosterone pathway and thus not generalizable to other agents in the same class, but the surprising lack of effect on carotid intima media thickness or coronary plaque volume implicate its primary mechanism of action, and highlight the complexity of the factors governing reverse cholesterol transport by HDL-C.(4)

And recent trials in diabetes management have highlighted the unpredictability and risks involved in manipulation of even the most well-established of risk factors.  In Ending Aging, our popular book on the theory and platform of regenerative engineering, we highlighted the surprising lack of benefit in patient quality of life of aggressive glycemic management in diabetes: despite the dramatic reduction in microvascular complications, patients experienced no improvement in their lives, due not only to the inconvenience, discomfort, and complexity of therapy, but side-effects directly attributable to primary mechanisms of action of antidiabetic agents themselves, including weight gain and hypoglycemic crises.

Subsequently, large-scale trials of aggressive management of glycemia in Type II diabetes not only failed to demonstrate the seemingly-foreordained benefits in cardiovascular outcomes, but suggested the possibility that it might increase mortality, and brought into question even the ability of tight glucose control to lower the risk of microvascular sequelae other than nephropathy, even as it increased substantially the relative risk of severe hypoglycemic events (5-7)

Perhaps even more surprising were the results of a series of recent large-scale trials evaluating the use of drug therapy for the other metabolic derangements (metabolic syndrome) characteristic of patients with diabetes or impaired glucose tolerance.(8-11)  Two of these trials(8,9)  found that as compared to usual blood pressure targets (<140 mm Hg), intensive management targeting systolic blood pressure < 120(8) or 130(9) mm Hg using a wide range of different agents did not reduce cardiovascular events, and increased total mortality. A third trial finds that correction of the atherogenic dyslipidemia of metabolic syndrome (elevated plasma triglycerides, low HDL-C, and small, dense LDL-C particles) by adding fenofibrate to simvastatin did not reduce the risk of adverse cardiovascular outcomes as compared with simvastatin alone, and may have increased the risk in women (P=0.01 for subgroup interaction).(10) And a study testing the addition of the angiotensin-receptor blocker valsartan to lifestyle modification in patients with impaired glucose tolerance found that while it reduced the rate of progression to diabetes over 5 y (33.1% vs 36.8%; absolute RR 3.7%), it did not reduce the rate of cardiovascular events relative to lifestyle modification plus placebo.(11)

The importance of these findings to considering different therapeutic strategies for targeting the biological aging process is obvious, and becomes even more so when one considers the even greater challenges to managing patients who have already suffered substantial aging damage. The epidemiological data are rife with paradoxical findings on the relationship between established disease risk factors and health outcomes in older adults, with the outcomes associated with overweight, hypertension, hyperinsulinemia, and others  declining in magnitude or even reversing relative to their relationships in younger persons(12-15). At least some of this is attributable to underlying structural and functional impairments caused by biological aging, making the appropriate medical management of older patients fraught. Taking the immediate case of diabetes, older diabetics have lower wright than younger patients, with underlying loss of lean mass and a relative increase in adipose tissue, and have greater beta-cell loss and an reduced insulin secretory response to glucose load, while having a more impaired glucagon response to hypoglycemia than younger subjects and thus a greater risk of neuroglycopenia, and having a lower life expectancy(16) Together, these factors increase the risks associated with glucose management in older subjects and commend less aggressive targets to clinicians,(16) even as older adults are at the most immediate risk of diabetic morbidity and mortality.

Looking Back, Stepping Forward

Even in the targeting of metabolic pathways with well-established causal roles in disease progression, then, recent evidence is showing that we are approaching the limits of the old paradigm of therapeutic development, particularly for those who have already undergone significant biological aging. Regenerative engineering provides a novel heuristic to bring forward the next great leaps in health  and longevity. By narrowly targeting the inert damage of aging to biomolecules, cells, and tissues for removal, repair, replacement, or aetiopathological obviation,  the link between metabolic processes and rising age-related disease, disability, and mortality can be severed directly, rather than partly mitigated at the expense of perturbing the activity and homeostatic regulation of those processes. Moreover, the fact that these new therapeutics would not only retard the age-related progress of pathology, but arrest and in principle reverse their underlying structural basis, they offer the prospect for dramatically-improved prognosis late in life, precisely when the burden of such damage is highest and the efficacy of metabolically-based intervention is most hampered by the underlying degradation of the very structures and pathways that it targets for manipulation.

Societies worldwide are undergoing a dramatic demographic shift, in which persons of what have heretofore been unusually-advanced age will take up an ever-rising and soon genuinely unprecedented share of the population.  If biological aging and its underlying structural and functional degradation is allowed to continue under its normal course, the age-related rise in disease and disability is slated to bring unprecedented challenges to societies, as health care costs per capita rise and productivity evaporates, even as the physical, emotional, and economic burden of patients and families consumes the resources and creative capacity of individuals. As we reach the limits of the old paradigm, SENS Foundation is committed to dissemination of the new one, and to the development and widespread adoption of the platform therapies on the most aggressive possible pace.

References

1. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G. Time to talk SENS: critiquing the immutability of human aging. Ann N Y Acad Sci 2002;959:452-462.

2. de Grey AD. An engineer’s approach to the development of real anti-aging medicine. Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1.

3. de Grey AD. Living to 100 and maybe much longer: the engineering and biotechnology of life-extension medicine and when it may arrive. In: Proceedings of the 6th International Conference on Intelligent Processing and Manufacturing of Materials (J.A. Meech, ed.), 2008, in press.

4. von Eckardstein A. Implications of torcetrapib failure for the future of HDL therapy: is HDL-cholesterol the right target? Expert Rev Cardiovasc Ther. 2010 Mar;8(3):345-58.

5. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59.

6. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72.

7. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39.

8. The ACCORD Study Group. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. N Engl J Med. 2010 Mar 14. [Epub ahead of print]. DOI: 10.1056/NEJMoa1001286

9. Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AL, Denardo SJ, Bakris GL, Pepine CJ. Rethinking Lower BP Goals for Diabetics with Documented Coronary Artery Disease: Findings from the INternational VErapamil SR – Trandolapril STudy (INVEST). American College of Cardiology 59th Annual Scientific Session, March 14-16, 2010, Atlanta, GA. Presentation Number: 3010-10. Presentation Time: Sunday, Mar 14, 2010, 8:34 AM – 8:46 AM

10. The ACCORD Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010 Mar 18. [Epub ahead of print]. DOI: 10.1056/NEJMoa1001282

11. The NAVIGATOR Study Group. Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med. 2010 Mar 29. [Epub ahead of print]. DOI: 10.1056/NEJMoa1001121

12. Euser SM, van Bemmel T, Schram MT, Gussekloo J, Hofman A, Westendorp RG, Breteler MM. The effect of age on the association between blood pressure and cognitive function later in life. J Am Geriatr Soc. 2009 Jul;57(7):1232-7.

13. Vischer UM, Safar ME, Safar H, Iaria P, Le Dudal K, Henry O, Herrmann FR, Ducimetière P, Blacher J. Cardiometabolic determinants of mortality in a geriatric population: is there a “reverse metabolic syndrome”? Diabetes Metab. 2009 Apr;35(2):108-14.

14. Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc. 2005 Feb;53(2):219-26.

15. Abbott RD, Curb JD, Rodriguez BL, Masaki KH, Yano K, Schatz IJ, Ross GW, Petrovitch H. Age-related changes in risk factor effects on the incidence of coronary heart disease. Ann Epidemiol. 2002 Apr;12(3):173-81.

16. Sood A, Aron DC. Glycemic Control in Older Adults: Applying Recent Evidence to Clinical Practice. Geriatr Aging. 2009 Apr;12(3):130-134.

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