TOWARDS THE UNIFYING HYPOTHESIS OF MANAGED ANTIAGING:

A gynecologist – the ultimate “midwife” of fertility, childbirth and womens’ successful midlife – asks: what are the pathogenetic mechanisms common to   the increasing fractures,   increasing stroke-cardiovascular and malignant  disease in the aging?

 

 It goes without saying that we humans are  our own worst enemies and the greatest threat to heathy survival of life. But bad choices and diet-lifestyle, Silent Spring,  and Oryx and Crake  aside:

 

CANCER – the least common clinically, that kills or cripples below 5%- is perhaps  easier to generalize: poisons like smoking, alcohol and asbestos aside, the common cancers  of the latter half of life  – the sex-hormone-related cancers- generally take decades to reach clinical significance, and involve many mechanisms including genetic, environmental, alcohol, smoking, lack of exercise, dietary and above all, random mutations and progressive dysregulation of aging and the millieu interieur.

 

 It is common cause that in both longterm historical followup clinics (Byrd & Burch; Schleyer-Saunders; Gelfand; Greenblatt Gambrell et al; the Nurses Study); and   in the trials- the Womens’ Health Initiative (2002, 2004) and the Oulu trial (Heikkinen 2006), women randomized to  appropriate conservative dose  oral estrogen-progestin from menopause and followed for up to 10 or more years had virtually one-third reduction in all common major diseases including breast and colon cancer, fractures, cardiovascular and dementing diseases, and in cancer- and all-cause mortality. Men followed for a decade and more from initiation of appropriate parenteral testosterone supplementation have similar striking reduction in prostate cancer and in cancer-and all-cause mortality (Behre & Nieschlag Germany; Carruthers London; Kaufman USA)  

 

CARDIOVASCULAR-STROKE DISEASE: it has been recognised for decades that  antioxidants,  and the three antihomocysteine vitamins (B6 B9 B12), and  the 150year old nitric oxide promoter nitroglycerin  NG are major benefit against chronic CVD and it’s  symptoms if not during acute myocardial infarction and stroke. NG remains the mainstay of treatment for angina.

     In acute myocardial infarction, the timing of intravenous NG seems to be crucial if it is to lessen morbidity and mortality (Jugdut Canada 1988), and similarly oral NG seemed to have no benefit following acute myocardial infarction  (Ishikawa  Japan 1996) except with heart failure (Fitzgerald 1990);  but  timeous transdermal NG may give beneficial improvement in cerebral bloodflow after subarachnoid hemorrhage (Reinert Switzerland 2006).

   There are apparently no  definitive randomized controlled trials on Medline  of chronic NG use in patients with chronic angina. But after angioplasty, restenosis angina responds well to NG (42% incidence)  compared to placebo (75%; p<0.003). NG lowered the repeat angiography rate from 23% to 4%.  (Doucet 2000).

 

OSTEOPOROSIS FRACTURES:

Ignoring  fracture incurred as a result of a stroke-induced fall, or visa versa; and ignoring disuse osteoporosis after stroke:

what factors contribute simultaneously to aging osteoporosis and stroke-cardiovascular disease CVD?

 

A forthcoming paper  (Kanawasa ea Japan Oct 2008)  “suggests that metformin can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signalling pathway, and that this drug might be beneficial for not only diabetes but also osteoporosis by promoting bone formation”. It is common cause that  diabetes is associated with weaker bones and more fractures (Yamamoto 2006).

 

Metformin (Werner & Bell  1922) is dimethylguanidine- the only  synthetic drug (a tagged  antihyperglycemic  extract of  the galega officinalis plant) that has been proven to be a panacea against virtually all major diseases, a heavy-metal chelating,  antimicrobial fibrinolytic antineoplastic antihypertensive antioxidant   insulin sensitizer (without increasing C peptide)  that also reduces lipidemia;  and  bone resorption  (and thus unblocks  obesity-related delayed adolescent  growth) via promotion of nitric oxide synthase- possibly via AMP(Kim 2007).  It is the only designer drug  ever that has been proven in a 20 year randomized controlled trial RCT (mean 13.6yrs- the UKPDS, Holman ea 1998) to reduce all major adverse events including cancer and allcause mortality by 36% in diabetics; and reduce new diabetes by about 50% (30 – 70%) in major prevention trials in prediabetics over a mean of about 3 years in the USA, India and Chinese Diabetes Prevention Programs- without a singe major adverse effect. No other designer drug for chronic prevention  can claim such multisystemic benefits and lack of adverse effects in sensible tolerable dose.

 

By contrast, Osdoby ea  1994 reported that  the nitric oxide inhibitor “aminoguanidine also caused a loss of bone mineral density – Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity”.  So while aminoguanidine was promoted a decade ago  as an antiaging antidiabetic drug against AGES Advanced Glycation  Endproducts   it has not  replaced metformin – despite promises, and thousands of papers  about it on Medline dating back to 1950, no clinical trial results have in fact been published  on Medline showing  aminoguanidine has any significant  longterm benefits.   The severe toxicity  reasons  (the ACTION ll trial) for this are detailed by Montagnani 2008.

 

Nitric oxide   is a key vasodilator, neurotransmitter and immunomodulator; it’s therapeutic level is boosted by nitroglycerine; metformin (Kanazawa 2008); human sex hormones and arginine.. Nobel prizewinner Ferid Murad ea 2008 note that “NO-mediated signalling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defence), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signalling.”      So, as with oxygen, vitamins, minerals, biologicals, foods, alcohol  and all therapeutics, balance – the right amount- is everything.

 

Interestingly, while arginine and appropriate testosterone-estrogen supplements usually boost insulin sensitivity as well as  low growth hormone HGH levels and thus anabolism in bone, muscle etc, a nitric oxide promoter eg nitroglycerin in its own right  has the same benefit as ERT in preserving good bone mass (Hao ea China 2005). This was already shown in chicks by Osdoby ea 1994,  based on a postulate by MacIntyre ea 1991 . – who subsequently demonstrated this in rats (MacIntyre 2003).  

 

Estrogen is a known immunostimulator  whereas progesterone and testosterone are known immunomodulators.    In vitro, estrogen too may have  a dimorphic effect on nitric oxide (Walsh 2003; Shih 2006; Richette 2007).  But in postmenopausal women transdermal or oral  ERT  with or without cyclic progestin for 6 – months increases NO levels (Serin 2001; Kesim 2005).

 

Pance 2006 notes that “estrogen and progesterone  regulate the nitric oxide synthases (NOS) and, in turn, the NO produced has profound consequences on tumor cell homeostasis. On one hand, estrogen increases the activity of endothelial NOS (eNOS or NOSIII), while progesterone activates inducible NOS (iNOS or NOSII) expression. The data presented suggest that the low levels of NO produced by NOSIII mediate the proliferative effect of estrogen. On the other hand, the increase in apoptosis in response to progesterone could implicate the high levels of NO produced by induction of NOSII expression”

 

                Testosterone on the other hand is the well-known crucial  erectile stimulator of nitric oxide synthetase   (Shabsingh 2004)  . 

 

So  apart from genetic programming and accumulating levels of environmental toxins, there are  at least six  possible pathophysiologies common to  the  preventible aging comorbidities of  apoptosis, fattening-diabetes-cancer; osteoporosis-fractures, and CVD-stroke:

*catabolism by gonadopause deficiency without a balancing fall in catabolic cortisol levels;

*nitric oxide depletion;

*increased reactive oxygen species ROS due to depleting endogenous and dietary antioxidants; 

*common aging-related deficiency of minerals eg magnesium, zinc,chromium, lithium; vitamins; and human biologicals eg    chondroglucosamine, CoQ10, carnitine, ribose, arginine, carnosine, Nacetylcysteine;  

*insulin resistance – prediabetes, metabolic syndrome, diabetes; and

*accumulating multiple metal overload eg cadmium, iron, aluminium, mercury, lead, arsenic copper (even zinc and iron)  from  smoking, food and environmental  pollution  that can simultaneously promote cancer, neurovascular  and osteoporosis problems

 

Obviously the basket of natural supplements-  fish oil, cal-mag zinc boron, the vitamins A ( bcarotene) to K, and the human biologicals proline, CoQ10, arginine, ribose, carnitine  and appropriate  hormone balance with eg testosterone-estradiol, growth hormone, and galega extract,  are trophic in improving anabolism, antioxidation, optimal NO levels and preventing AGES, atheroma and arteriosclerosis as well as collagen and mineral loss from diverse muscle and bone – ie preventing many  of the risk factors for both fractures (frailty, weak  bones and muscles – skeletal and smooth ie  gastrointestinal and heart ) and vascular disease .

 

Given the common pathogenetic factors of all the common major aging diseases,  one should simply add natural arginine glutamine and proline,  in addition to the vitamins, minerals, glucosamine-chondroitin, and the other natural insulin sensitizers eg N acetyl cysteine, ribose, carnitine, CoQ10 and galega officinalis, to the natural supplements  to combat all aging diseases; and when hypogonadism becomes likely- with chronic illness, or from middle age- add appropriate parenteral balanced  physiological-dose testosterone-estradiol- progesterone to restore the average levels of healthy slim youthful adults.

 

While some of these above  may be chelators in their own right, the high prevalence of metal overload may justify routine addition to supplements (within recognized tolerance and safe limits)  of extra harmless putative chelators like calcium EDTA, carnitine, bromelain,  garlic,  malic acid, cysteine, lipoic acid, vitamin C, selenium, thiamine, magnesium, selenium, zinc and bromelain.

 

ndb

 

The first comment attached below is appropriately from

Professor  Frederick Naftolin MD, PhD, FACOG, FRCOG

past Chairman of OB/GYN at McGill and Yale Universities, then Prof of Biology at Yale,
now Professor of Obstetrics and Gynecology
Director, Reproductive Biology Research
Co-director Interdisciplinary program in Menopause Medicine
New York University School of Medicine

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2 responses to “TOWARDS THE UNIFYING HYPOTHESIS OF MANAGED ANTIAGING:

  1. While these suggestions are of considerable individual merit, the greater issue is to recognize that the millennium sealed the chapter on treatment as a viable primary health strategy for mankind. This century and those to follow will require choices, redistribution of resources and new definitions for success. All this will have to go on while we are fighting the war on clinical disease, absorbing the flight from poor to not-so-poor areas, social upheaval and other problems that are of this world.

    We have largely beaten natural selection as a force in our destiny, and are truly masters of the universe. This means that the burden is squarely on us to decide who lives and who dies, when and how. And, the results of individual decisions pale against the impact of genetic engineering by the use of antibiotics, metabolic regulation, etc.

    The chief enemy is tribalism, a hold-over from the old, Darwinian days. Tribalism is putting and keeping the world in turmoil. But,” better things for better lining” keep coming and will only accelerate the differentiation between the haves and have-nots. Yet, “we are all in the same (larger) boat.” We must give up tribalism and redistribute turf. Now that it is in our hands to decide our fate, we must accept that there can be no racial or sexual inequalities and that health and education are public utilities. Like war not being left to the generals, there must be more engagement of more non-health-care leaders in this process. They need education and a world view of the issues. All need the courage to change thinking and action.

    In the instance of health care, doctors, who have been so privileged to serve and be served during the past must reorganize around prevention and to make the post-reproductive years (presently approaching one-half of life) seamless. This means a melding of geriatrics with all of the primary care disciplines that feed geriatrics. There needs to be a world-wide epiphany and coming together, not a solidification of “markets” and constituencies.

    The future may or may not be bright; but, it is our future and we had better stop putting the onus on anyone but our selves to get it right.

    Yes, the things mentioned in this letter are useful, but they are Band-Aids for an ever more gaping wound. Let’s not kid ourselves; we need to grow into the life that we have made for our selves. No one can do that for us, and no one will. “Physician, heal thyself” is still good advice.

  2. Pingback: TOWARDS MANAGED AGING part 3 « Healthspanlife - the Official Life! Blog

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