The Telomere Shortening theory of aging fits in neatly as a component of the Aging as Programmed Epigenomic Changes theory. Other aging programs could involve age-related increases in NF-kappaB and P16. These and associated increases could lead to age-related Decline In Adult Stem Cell Differentiation, an aspect of the Stem Cell Supply Chain Breakdown theory of aging. The basis for regeneration of aging tissues is provided by adult stem cells. P16 protects against cancers but induces premature senescence in progenitor cells. Progenitor stem cells play important roles in the maintenance of homeostasis in cardiac and other tissues and organ maintenance and repair after injury.

In the traditional view,Oxidative Damage has been seen as an important driver of aging and implicated in the processes of several of the other theories of aging. We knew for example that Oxidative Damage leads to Telomere Shortening. It is also a major cause of Cell DNA Damage which in turn can lead to Susceptibility to Cancers. Mitochondrial Damage can be brought about through Oxidative Damage or via signaling pathways conditioned by Programmed Epigenomic Changes. In turn, faulty mitochondrial functioning can lead to a number of metabolic disease conditions and faulty mitochondrial signaling can lead to errors in apoptosis and a multiplicity of disease susceptibilities including Susceptibility to Cancers and Susceptibility to Cardiovascular Disease. Just about every cellular process involves the operation of multiple feedback loops. Whether and how much exposure to oxidative conditions actually leads to aging depends on numerous factors such as the availability of antioxidant defenses. Natural antioxidant defenses decline with aging, another aspect of the epigenomic aging program driven by changes in the chromatin of cells which accumulate with age. As pointed out in the blog entry End of the free radical theory of aging, however, the free radical theory of aging is itself in deep trouble and both free radicals and the use of antioxidant supplements have to be looked at in a much deeper manner.

The feedback loops between many body systems are so tightly interrelated that it is difficult to say where one theory leaves off and another one starts. Considering the Decline in hormone levels and the Neurological degeneration theories, for example, it has long been known that "the neuroendocrine and immune systems are intimately integrated into one system that provides a complex homeostatic network(ref)." And auto-immune diseases like lupus erythematosus and rheumatoid arthritis can involve Chronic inflammation.

A simplified example of how seven of the aging theories link together is that Oxidative Damage activates NF-kappaB (the Programmed Epigenomic Changes theory of aging) resulting in expression of pro-inflammatory genes leading to a chronic inflammatory response. The inflammatory response is a mechanism in turn deeply implicated in Susceptibility to Cancers and Susceptibility to Cardiovascular Diseases, and Neurological Degeneration. Nothing is really simple, however. Whether a cancer cell is subject to apoptosis or proliferates is dependent on other epigenomic considerations such as the availability of a strong P16 or P53 defense.

Chronic Inflammation is a part of an aging-related program that can be triggered by numerous stimuli, is generally mediated by a gene activation sequence triggered by overexpression of NF-kappaB and related factors, and is an entry portal to several other of the aging related conditions including Tissue Glycation, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and Susceptibility to Cancers. Telomere Shortening and Damage leads in time to cell senescence, apoptosis and mutations which in turn generate a number of the epigenomic-mediated aging conditions including Immune System Deterioriation, Susceptibility To Cancers, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and atrophy of hormone-producing organs leading to Declines in Hormone Levels. The later is an example of the feedback between cell-level and organ-level functioning showing how damage on one level can cause damage on the other level as well.

The pathways affecting aging are complex and multiply interconnected. And gene expression as well as activation of factors like NF-kappaB are themselves dependent on the state of the epigenome and are therefore functions of age.

During chronic diseases there is generally a decline in the functioning of adult stem cells, cells essential for organ repair and regeneration. The same happens in the process of aging. The survival of adult stem cells and their ability to differentiate depends on the presence of growth regulatory signals and NF-kappaB plays an important epigenomic role in this process. Also, Telomere Shortening and Damage in adult stem cells may be a major cause of age-related Decline In Adult Stem Cell Differentiation.

Telomere Shortening and Damage itself, on the other hand, appears to be not inexorable because long-term population studies show that for some individuals telomeres actually get longer over substantial time periods. Telomere shortening may be caused by stress and oxidation, but may be mitigated by effective expression of telomerase which in turn requires the availability of telomerase binding proteins which is dependent on the states of histone acetylation of the DNA binding sites for these proteins – e.g. on their epigenomic states. Another of the Sirtuins, SIR6, appears to play a key role in maintaining telomeric integrity by preventing telomere looping and other damaging conditions, another link between the Programmed Epigenomic Changes and the Telomere Shortening and Damage theories of aging.

On the surface it appears that the 14^th theory of aging Stem Cell Supply Chain Breakdown is very different than the  12^th theory Telomere Shortening. And these two theories seem to be different than the 2^nd  theory Cell DNA Damage.  However, a number of recent studies show a growing web of relationships among these theories.  For example,  telomeric dysfunction may be at the heart of the decreasing capability of stem and progenitor cells to replicate and renew tissues with increasing age (ref,ref,ref,ref).  The studies have looked at telomere shortening in hematopoietic stem cells (HSC), mesenchymal progenitor cells, osteoblasts and neural progenitor cells.   One study suggests that proteins secreted from telomere-dysfunctional bone-marrow cells may provide accurate biomarkers of aging. As usual when it comes to aging, there are wheels within wheels.  Among the many cellular proteins that influence telomere structure, function and enlongation are the telomerase binding factors TRF1 and TRF2 and less-directly shelterin-complex, PinX, Apollo and tankyrase(ref).  TRF2seems to play a key role in the differentiation of neural stem cells(ref) as well as in cancer proliferation.  In a closely related front, telomerase expression and TRF2 seem to play key roles in maintenance of DNA repair mechanisms in neural cells and stem cells(ref). 

Lipofuscin Accumulation is driven by a history of metabolic processes dependent on the mitochondria, facilitated by oxidative stress and conditioned by the availability of substances which pump lipofuscin out of cells which depend on the epigenomic states of the cells. Declines in Hormone Levels may be the result of some kind of epigenomic program as well as a consequence of hormone-producing organ deterioration. In fact hormones are intermediary epigenomic factors because they themselves lead to changes in gene expression that affect the production of other hormones as well as disease susceptibilities and other markers of aging.

Additional discussions of how the theories of aging link to one another are provided in the Note New evidence linking the aging theories and in the blog entry Linking up the theories of aging. The Note describes crossover links among at least four of the theories: Programmed genetic changes, Oxidative damage to tissues, Chronic inflammation, and Telomere shortening and damage. The blog entry describes a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation (later subsumed under Stem Cell Supply Chain Breakdown) theories. In November 2009 I added a blog post that identified another important link between two of the theories: Breakthrough telomere research finding. As telomeres become critically short, the gene expression in affected cells changes so as to induce senescence and at the same time to affect the maintenance of epigenomic memory and nuclear organization, thereby contributing to organismal aging on the whole-animal level. Critically short telomeres deregulate epigenomic control and alter gene expression so as to create the changes we know as “aging.” A more-recent February 2011 blog entry JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging demonstrates how epigenetics provides a powerful integrative framework that applies across most if not all the other theories of aging.

The above is just a starting sampler of known links among the theories of aging. It seems that research revealing a new link or shedding new light on existing ones is reported almost every week. As this happens, we are getting closer to understanding aging and what can be done about it. While we are not there yet we are getting closer to a unified theory of aging. Also it is already clear how an anti-aging firewall intervention intended to address aging according to one theory usually addresses aging according to several other of the theories as well. For example, a number of the anti-inflammatory phyto substances like curcumin inhibit the expression of NF-kappaB and addresses aging according in multiple other dimensions beyond control of inflammation. The same is essentially true of most of the supplements in the combined firewall, they being antioxidants and/or inhibitors of NF-kappaB.

My firewall approach to longevity is a simple and practical one.  When I drafted the first version of this document in 2008, I saw this approach as appropriate for older people given the current state of knowledge and relative ignorance compared to what will be known in coming decades. And I still see it that way. However, my views have been far from static. As I have learned more about the sciences of longevity and the overall state of knowledge has expanded, I have continued to revise the firewalls regimens. For example, by November of 2010 there was more published knowledge about telomerase biology and telomerase and the depth of my personal knowledge about this field had increased considerably. Based on this knowledge I decided to discontinue use of cycloastragenol or any other specialized commercial "telomerase activator." See the March 2011 blog entry The epigenetic regulation of telomeres.  Further, in September 2011 I published entries in my blog suggesting the end of the free radical theory of aging(ref)(ref), a radical shift that is likely to produce ongoing controversy.

I started working with primitive computers in 1951 and have spent much of my previous career in computer-related work.  The science and practice of longevity seems to be now (2011) in about the same stage now as was the computer field back in 1958 -  the same kind of excitement, the same rapid influx of new people into the field, the same competition among new ideas, the same rapidly increasing rate of knowledge and practical progress.

Given the mechanisms of aging characterized in each of the theories of aging, I lay out what I think can be done now to protect against those mechanisms.  That is, for each theory of aging, I seek to identify a protective “firewall” that can be practically implemented today that will likely retard, stop or even reverse aging according to that theory.  I am talking about lifestyle modifications and use of dietary supplements.  In fact I am describing a highly personal matter – what I have been doing to prolong my life and live fully with a high quality of life while I am still alive.  I have been studying this matter for 15 years now, and have gradually come to the program I am describing.  This program is neither complete nor final nor guaranteed to work. I continue to modify it as new research findings come to my attention.  It is quite different now than it was almost four years ago when I created the first version of this treatise.  I mention the research bases for the firewalls and offer further caveats at the end of the treatise.

III.     FIREWALLS AGAINST AGING AND AGE-RELATED DISEASES

My general approach is to construct an in-depth defense (a firewall) against the causes of aging attributable to each theory of aging or cause of aging death, to the extent that is possible given current knowledge.  A firewall can be compared to an infantry line of military defense.  Rifles, machine guns, grenades, land mines, rocket launchers, fox holes and camouflage can be useful parts of such a line of defense. But it would not be wise to try to construct a defensive position using only one of these kinds of weapons, say only machine guns.  Similarly an adequate defense against free radicals cannot be based on using only one antioxidant like vitamin C.  Most of the supplements I suggest are pluripotent, i.e. are effective against many conditions.   For example, in animal studies resveratrol has very strong positive effects on reducing heart inflammation, preventing cardiovascular disease, supporting bone structure and function, and maintaining loco-motor and balance activity. However, no one substance is a sure cure or preventative for a specific cause of death.  Each substance works through its own biochemical mechanisms and has its own role in a protective firewall.  I have attempted to construct practical firewalls that each contain multiple defensive measures, limited only by the state of research knowledge, by my own knowledge, and by the practical availability of firewall substances.

1. Oxidative Damage Firewall

The traditional view is that anti-oxidants are highly effective in scavenging ROS and mitigating their damage. Therefore, taking antioxidant supplements has been seen as generally health-promoting if not life-extending. However, as we have developed much more sophisticated understanding of cellular processes, this view has become seriously challenged. "Long-lived organisms, like humans, have developed very sophisticated enzymatic systems for controlling and utilizing radicals. These natural antioxidant defenses are much more effective than crude antioxidant supplements which have not been shown to be effective at preventing aging, or any degenerative disease. Some clinical trials of antioxidant supplementation have even found harmful effects(ref)."

That taking antioxidants may actually create harm has been telegraphed in my earlier blog entries. Over a year ago I reported on a publication How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). “Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman’s free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. "

Hormesis is a natural process, having to do with responses to stresses, disease resistance and longevity, a process that plays a critical role in all successful species, plant and animal, from the smallest bacteria to the biggest animals. Hormesis is a fundamental and universal process of biology. It is essential for both evolution and survival of individuals and species. Although hormesis was unknown to me when I drafted the first version of this treatise, I now (April 2013) see hormesis as extremely important. This importance is not only for understanding what is going on in health, diseases and aging, but also for suggesting practical health and longevity-enhancing interventions. For the reader unfamiliar with hormesis, I suggest, to start, viewing the presentations which can be downloaded from the recent blog entry Multifactorial hormesis - Powerpoint presentation. See also the blog entry Multifactorial hormesis.

One type of hormesis has to do with the body's natural response to oxidative stress whereby, up to a point, modest amounts of oxidative stress are good for you and confer a number of beneficial health effects. So, hormesis dictates that oxidative stress is bad for you and may contribute to aging only if it is beyond a threshold level. Below that level it is good for you. This is quite contrary to the original theory of oxidative stress which held that free radicals at any level are bad for you. The evidence is quite clear that, in a number of species, a modest level of oxidative stress and hormesis also contributes to longevity. Two of the more-recent (September 2012) blog entries go into depth on the topic of ROS hormesis are Mitohormesis, and Radiation hormesis. Earlier (2009) blog entries on the topic were Hormesis and age retardation and Stress and longevity. The benefits of regular exercise are realized via stress-induced hornesis, so such exercise is an extremely important part of the oxidative damage firewall. The central pathway involved in the induction of ROS hormesis involves the transcription factor Nrf2, discussed below.

Most of the supplements I have previously listed in this section as antioxidants are pluripotent in their biological activities, substances that act through a multiplicity of biological pathways to produce documented health benefits. Whether such a substance is an anti-oxidant or not may not may be of secondary or of no importance to the key biological activities of that substance which might include activation of Nrf2 and activation pecific pathways like SIRT1 and inhibition of others like of NF-kappaB, not to mention epigenomic impact on methylation or histone acetylation and siRNAs. etc. This applies to food substances such as olive oil and walnuts as well to many of the firewall supplements such as curcumin and resveratrol. What seemed simple becomes very complex and yet very exciting.

I have been asked by others and have asked myself "“How can you simultaneously warn against indiscriminant antioxidant supplementation and at the same time so enthusiastically endorse consuming foods which have strong antioxidant capabilities, ones like broccoli, coffee, olive oil, chocolate, garlic, green tea and blueberries? And, if antioxidants are bad for you, how can you continue to advocate taking so many antioxidant supplements like curcumin, alpha-lipoic acid, ashwagandha, boswellia, ginger and resveratrol?” The answer to that question is provided in detail in the three blog entries * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects, * The pivotal role of Nrf2: Part 2 - foods, phyto-substances and other substances that turn on Nrf2, and * The pivotal role of Nrf2. Part 3: Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension?

There are hundreds of antioxidant substances, that is substances whose molecules are chemically capable of inhibiting ROS from being formed, or capable neutralizing ROS. While many such substances in my suggested anti-aging firewall list are incidentally antioxidants, being an antioxidant was not the central reason for including them in the firewall list. They are on the list for other research-based reasons, for example in many cases that they activate the Keap1-Nrf2 pathway and inhibit the inflammatory activities of NF-kappaB. . Blueberries, for example are commonly touted as good for you because they are excellent anti-oxidants. Actually, they consist of complex phyto substances that act through a multiplicity of channels, and produce a myriad of documented positive health impacts(ref) (ref). In a series of blog entries I have looked at a number of such substances that are nominally antioxidants, citing research relating to their modes of action and health benefits resulting from taking them. Beside blueberries, in my blog I have looked explicitly at olive oil, walnuts, dark chocolate, hot peppers, ginger, curcumin, resveratrol, caffeic acid, rosmarinic acid, grape seed extract, and bitter melon. Similarly many other plant-based phyto-substances with documented positive health impacts happen also to be anti-oxidants like green tea, garlic, boswellia serrata, cat's claw and lycopene. And I have reported also on certain non-phyto supplement substances that are much more than antioxidants, like l-carnosine, and PQQ.

It is no longer a sweeping game where antioxidant = good and radicals = bad, but neither do I believe that the opposite is true. Rather. I am suggesting that direct chemical antioxidant properties of substances may be fairly irrelevant compared to other properties and each substance must be examined for its specific activities. Further, I believe that circumstances can exist in which taking a strong mix of antioxidant supplements is probably well-justified , such as when one has had or will have a major exposure to radiation(ref).

I will be continuing to revise this section. For the moment, what follows for historical purposes is the material originally included in this section of the treatise. It describes the argument for using antioxidant supplements to defend against oxidative damage. But remember, most of the suggested substances do their good work via gene activation and inhibition and via epigenetic actions, not by simple direct chemical antioxidant actions on free radicals.

Lifestyle

Basically the program is to avoid circumstances that produce very large number of unnecessary free radicals (ROS) in the body.   But the situation is not that simple. X-rays or other stressors that arein small enough doses to be in the hormetic response range might actually be good for you.  Do not smoke and avoid breathing second-hand smoke.  Use protective clothing, sunglasses and sunscreen under outdoors sunny conditions.  Avoid exposure to heavy metals and toxic chemicals.  For example, avoid handling arsenic-containing pressure-treated lumber without gloves or breathing the smoke of it burning.  Adopt dietary habits featuring large amounts of fruits and vegetables, some fish, moderate consumption of meats and consciously limit eating foods that contain excessive omega-6 fatty and trans- fatty acids.  Cook foods only at moderate temperatures and avoid browned food.  Avoid fried foods, fast foods, hydrogenated oils and ones preserved with nitrites.  Eat mercury-containing fish like tuna or swordfish only once a week.  Use plenty of olive oil and drink ample amounts of green tea.  Good foods include blueberries, sardines, and broccoli.  Consume a moderate amount of dark chocolate daily – with 70% or greater cacao content.  Consume alcohol in moderation stress. A small glass of red wine at dinner might help. Consult my blog entries on hormesis for more details.

Supplements for the oxidative damage firewall

When I started out writing this document five years ago, I thought that taking exogenous antioxidants like Vitamin C was the way to deal with free radicals and ROS damage. My thinking about that has changed direction by 180 degrees as I learned more. Now I believe that the body's own anti-oxidants are effective in scavenging ROS and mitigating their damage. Further, there is research that consuming large quantities of anti-oxidants like Vitamin C can interfere with the body's own antioxidant defense system and have negative health consequences. I see the appropriate role of dietary supplements is supporting the body's own anti-oxidant defense systemnot exercising chemical anti-oxidation as rust removers would. For most of the supplements suggested here, they work by activating the Keap1-Nrf2 pathway which in turn activates a large number of stress-protetive genes, including genes for our body's own antioxidant defenses. Different antioxidants have different properties with respect to the kinds of ROS ions they can neutralize, their fat solubility, the tissues they penetrate, their effective duration in the body and their biochemical mechanisms of operation.

The body uses several different antioxidants as part of its own ROS defense system and I prefer doing the same rather than on relying on only one or two.  My current "antioxidant" regime includes phytosubstances that activate the Nrf2 pathway in the foods mentioned above and: Essential Fatty Acid oils (EFAs) focusing on Omega-3 oils, Vitamin D-3, the hormone melatonin and plant-derived substances (phytochemicals which might be known as flavinoids, carotenoids or polyphenols)  including resveratrol, curcumin, boswellia, ashwagandah, pycnogenol, green tea extract, olive leaf extract, lycopene, allicin and  OPC grape seed extract. While these are commonly refered to as "antioxidants." they are actually not that. These substances work through a number of different complicated channels to achieve their ROS-quenching and other health-producing impacts, particularly the Keap1-Nrf2 pathway.(ref) [4].

A basic tenant of my firewall philosophy is to use multiple different defense mechanisms whenever they are available.  I summarize the supplements I take daily and dosages in a table at the end of this article.

I touch on the subject of poisoning due to heavy metals and certain substances such as PCBs here.  Some of these poisons produce large quantities of ROS; some operate through additional channels of toxicity.  For example, it appears that exposure to heavy metals and arsenic reduces serum concentrations of carotenoids, reducing the body’s natural anti-oxidant defenses.  Such poisoning can lead to degeneration and premature aging according to a number of the age-related theories, including immune system deterioration, neurological degeneration, susceptibility to cancer and susceptibility to cardiovascular disease.  While acute poisoning with excessive blood serum levels of PCBs, lead, arsenic, cadmium or mercury requires intravenous chelation and other aggressive treatments, supplements can play a role in ongoing control of serum levels of these substances in healthy individuals and on the biological impacts of the presence of such toxins.  L-carnosine is an important element of my firewall defense against toxic heavy metals like cadmium, lead, and mercury since it has an ability to chelate them (literally, to grab on to and combine with the molecules of these metals so the kidney and liver can excrete them).  Further, according to animal experiments, certain antioxidants already in this firewall, vitamin C, alpha tocopherol, melatonin and alpha-lipoic acid in particular, can play roles in reducing the toxicity of heavy metals and PCBs, in some cases reducing it dramatically.   Other components of the firewall defense against toxic metals are mineral supplements that compete for absorption and compete metabolically with such metals.   For example, copper and selenium antagonize mercury.  Calcium helps reduce lead and zinc helps reduce cadmium.  Magnesium also appears to be very important for protecting cells from heavy metals.  Besides protecting cells from certain forms of ROS damage, magnesium appears to be important for the absorption and metabolism of other supplements in the anti-oxidant firewall, including vitamin C and E and the B vitamins. 

2. Cell DNA Damage Firewall

Lifestyle

Follow the basic advice I have already given above under the Oxidative Damages to Tissues firewall.

Supplements for the Cell DNA Damage firewall

The advice with respect to supplements is also the same.  Curcumin, ashwagandha, resveratrol and green tea in particular appear to have important properties in regulating P53, P21, CASP9 and other genes which control apoptosis, inhibition of cell growth and cell cycle arrest so as to maintain a line of cells in a healthy state.  These herbal substances act through complex biochemical and genetic pathways only now becoming understood, and are also important components of the firewall against cancers.   Resveratrol, a polyphenol found in grape skins and red wine, activates an ancient life-extending chain of genetic reactions that works across species in plants as well as animals - Xenohormesis.  It’s use can extend the life spans of small animals up to 30% and many researchers familiar with this substance take it regularly.  OPC and other polyphenols may exercise similar effects. The firewall for the 13th theory of aging (Programmed Genetic Changes) and the ability of thirty-nine of the firwall substances to inhibit activation of the nuclear factor NF-kappaB is particularly relevant to DNA protection. Alpha-lipoic acid and many other of the combined firewall substances work to block the binding of NF-kappaB to cellular DNA. The results can be multifold, ranging from increased apoptosis of cancer cells to reduction of diabetes or atherosclerosis to a younger and less-wrinkled skin.

3. Mitochondrial Damage Firewall

Lifestyle

Again, follow the advice already given.

Supplements for the mitochondrial DNA mutation firewall

Certain supplements have the capability to penetrate into the mitochondria and prevent oxidative damage(ref).  Acetyl-l-carnitine and alpha lipoic acid work synergistically(ref),(ref). This combination alone has been shown to extend the lives of some small animals by as much as 30%  The R isomer of alpha lipoic acid can facilitate repair of mitochondrial DNA according to one study. It appears that the combination of Acetyl-l-carnitine and R-alpha lipoic acid can exert a preventative effect against Parkinson's disease according to a recent cell-level study(ref). Research on this relatively new combination of mitochondrial antioxidants continues and further interesting results can be expected.  

Of course the previous list of supplements also applies, often in special ways. Resveratrol targets one of the enzymes that regulate the function of mitochondria, and has been shown to block high glucose–induced mitochondrial ROS production in certain animal cell lines. In the mitochondria. Coenzyme Q-10  is a key mediator for electron transfer and is a highly recommended supplement for people known to have a mitochondrial disease.  

Telomerase activation via use of an astragaloside IV extract, as described in the firewall for the Telomere Shortening and Damage theory of aging, also provides mitochondrial protection and is part of this firewall. Telomerase expression does not always lengthen telomeres. When a cell is under stress, telomerase (actually its catalytic subunit TERT) migrates into the mitochondria. There TERT plays a DNA-protective role and improves mitochondrial functioning. Thia quote is from a study report entitled Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. “While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner. Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, mtDNA is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.” Several other recent research reports supports this finding. For example, see the June 2009 publication Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Here is a May 2009 review study on the same issue.

4. Tissue Glycation Firewall

Lifestyle

Minimize eating substances having a high glycemic index, that is, sugars and substances your body converts to sugars. There are multiple reasons for this including and going beyond minimization of glycation within the body. Consuming low glycemic-index foods is very important for weight control, cardiovascular health and control of diabetes. High serum levels of simple sugars can contribute to the proliferation of cancers. Further, consuming high glycemic-index foods can lead to drastic changes in blood sugar levels affecting mental balance and one's sense of well being. It is a good idea to become familiar with the glycemic index so as to learn about the foods to avoid and other foods that can be substituted for them. For example,products containing corn syrup, soft drinks, sweetened breakfast cereals, white bread, refined-flour pastas and sugary deserts rank high on the glycemic scale, while whole-grain cereals, fruits, leafy vegetables and soybeans rank lower on the scale.

Specifically with respect to glycation, avoid eating large amounts of substances where glycation has occurred, including burned or browned meats and fast foods of all kinds.  Eat foods cooked at lower temperature, avoiding those cooked by grilling, broiling and frying. Wear sunglasses to help protect against cataracts.

Some lifestyle adoptions offer longevity benefits that cut across several of the theories of aging, including inflammation.  A good example is the so-called Mediterranean diet, which I am well aware of because I recently returned from two weeks in southern Italy.  This diet features eating lots of vegetables and fruits, lean protein, fish, whole-grain pasta, lots of olive oil and moderate amounts of red wine.  Besides reduced inflammation and glycation, there is strong clinical evidence that this diet enhances weight management, reduces stress, helps prevent cardiovascular diseases and cancers, improves blood sugar metabolism, helps neutralize ROS, and yields improved sugar metabolism that impacts on glycation.  I ate more generously than normal while in Italy, but yet lost weight.

Supplements for the tissue glycation firewall

Two supplements are of particular interest. The first of these is l-carnosine. It acts both to prevent glycation in the body and to stimulate enzyme reactions that break up and eliminate already-formed AGEs. Carnosine is an effective scavenger of several unsaturated aldehydes (sugars) which induce DNA-protein and protein-protein cross-linking seen in ischemic-damaged cardiovascular tissues, in Alzheimer's disease and other neurodegenerative disorders, and in various inflammatory diseases. The other substance is a fat-soluble form of the vitamin B-1 known as benfotiamine.  Benfotiamine inhibits the formation of AGEs.  These firewall substances are particularly important for diabetics.  They can mitigate or block the biochemical processes that lead to nerve, kidney, retinal and vascular damage associated with high blood sugar levels.  Magnesium, another component of this as well as other firewalls, helps regulate blood sugar levels and prevent glycation.  Other supplements in the overall list also contribute to this firewall, such as Vitamin C.  Vitamin C is important for collagen metabolism; it is believed to increase the level of pro-collagen messenger RNA, and facilitates "hydroxylation," a process that facilitates collagen molecules to organize themselves in the best protective configuration to resist damage. There is much laboratory evidence that acetyl-l-carnitine helps to reduce glycation in eye lenses, the cause of cataracts. Phosphatidylcholine, previously a firewall substance, is a major constituent of cell membranes, and also plays a role in membrane-mediated cell signalling.

5. Lipofuscin Accumulation Firewall

Lifestyle

Protection against oxidative damage is a key strategy for minimizing the production of llipofuscin. So, see the firewall for the oxidative damage theory of aging. Ihave no particular additional advice in this regard except to emphasize the importance of wearing sunglasses in sunlight to protect the retina from buildup of lipofuscin and druzen that can lead to macular degeneration.

Supplements for the lipofuscin accumulation firewall

Several of the antioxidants already mentioned function so as to reduce levels of lipofuscin accumulation in brain and other cells, including alpha-lipoic acid, CoQ10 and curcumin. Piracetam, another firewall component, appears to significantly decrease the formation of lipofuscin in neurons. I take two supplements which have a capability to pump lipofuscin out of cells.  One is meclofenoxate (centrophenoxine) a ‘smart drug” used in Europe to treat symptoms of senile dementia and Alzheimer’s disease. The other is acetyl-l-carnitine, a pluripotent antioxidant also useful for mitochondrial health. 

6. Chronic Inflammation Firewall

Lifestyle

Follow the suggestions previously made with respect to dietary habits.  The Mediterranean diet can be very helpful.

Supplements for the chronic inflammation firewall

Some of  the antioxidants previously mentioned have anti-inflammatory properties.  For example, Vitamin C assists in the breaking down of histamine, an inflammatory substance produced by many allergic reactions. Vitamin D-3 suppresses the production of cytokines (inflammation-producing messenger substances exuded by cells) and is an important component of the firewall.  Several of the the plant-derived phytochemicals are powerful anti-inflammatories, including aswagandah and boswellia.   These as well as green tea and use of green tea supplements are important components of the firewall against rheumatoid arthritis, osteoarthritis, tensovitis and other inflammatory diseases. Bromelain is another anti-inflammatory phyto-substance in the firewall shown to be effective against joint inflammation. Several of these plant-based substances including ginger and curcumin are COX-2 enzyme inhibitors but, being natural substances, tend not to have the side effects of drugs designed for that purpose.

There is increasing understanding of the genetic mechanisms underlying inflammation and how supplements in the firewall can intervene in inflammatory processes. An example is low-level chronic inflammation in obese individuals. Their adipocyte (fat cell) genes express cytokines (TNF-alpha, IL-1beta, IL-6 and COX-2) implicated in cardiovascular diseases, type 2 diabetes and other pathological conditions. Curcumin and resveratrol are among the phyto-substances able to inhibit TNFalpha-activated NF-kappaB signaling in adipocytes and as a result significantly reduce their inflammatory cytokine expression. In fact, some 39 substances in the combined firewall are inhibitors of NF-kappaB cell signalling and therefore work to inhibit inflammation. See the discussion under the Programmed Genetic Changes Firewall. .

Control of tissue glycation and production of AGEs is important for control of inflammation. As saturation of tissues with AGEs begins to reach an advanced stage in older individuals, aggressive use of supplements to reduce them can be necessary to control the source of inflammation. See the tissue glycation firewall.

Also, potassium is part of this firewall.  It can help the management of inflammation and some researchers believe it is very important for controlling arthritis.  These anti-inflammatories together with vitamin B-6 helped me to vanish what once was a serious and worsening case of rheumatoid arthritis, much to the amazement of my rhumatologist . They were far more effective in this regard than the toxic anti-arthritic medicines that had been prescribed for me.  From time to time in my life I have also been plagued with tensovitis and carpal tunnel conditions.  These have also nearly disappeared since I have adjusted my regimes of these anti-inflammatory substances about seven months ago.

7. Immune System Compromise Firewall

Lifestyle

The main thing is to adopt a lifestyle which supports regular functioning of the immune system and avoids unnecessary challenges to it.  Sleep at least seven and a half hours a night on a regular schedule, avoid chronically stressful situations, do mild cardiac exercise at least a half-hour each day, avoid situations likely to lead to infections,  Treat infections promptly with lots of rest.  And of course, avoid oxidative challenge as outlined previously. Having good family and friend relationships and a positive mental attitude can also help.  Meditation and Yoga can also be powerful tools, although I do not practice these myself.

Supplements for the immune system compromise firewall

Antioxidants like those already mentioned contribute to lessening the load on the immune system.  For example, the activity of antibodies and immune system cells such as phagocytes and neutrophils is stimulated by Vitamin C.   In addition I take certain plant-related substances which specifically enhance immune system functioning as well as protect against infectious diseases.  These include astragalus extract, the most concentrated form I can find, olive leaf extract and allicin. Each of these have significant antibacterial and/or antiviral properties. Allicin is effective in killing many strains of methicillin-resistant staphylococcus aureus (MRSA), the forms of staph resistant to conventional antibiotics. Olive leaf extract has strong antiviral properties and, in the laboratory at least, inhibits acute infection and cell-to-cell transmission of HIV-1. Astragalus has demonstrated a wide range of immunopotentiating effects and has proven efficacious as an adjunct cancer therapy.  Among other capabilities, astragalus protects against common colds and many virus strains.  Contrary to a long-established pattern, I have had only one common cold since I started taking substantial doses of astragalus two years ago. It appears that astragalus extract and its derivative astragaloside IV have important immuno-modulating effects. See the discussion in the firewall section for the Telomere Shortning and Damage theory of aging. Also, studies show that several of the firewall substances tend to have synergistic effects on immune system functioning. For example. in chickens at least it appears that astragalus polysaccharides and probiotics work together to support immunity(ref). The blog entry Vitamin D3 and the immune response describes new research(ref) published in 2010 indicating how vitamin D3 is essential for the mobilization of a T-cell immune response.

8. Neurological Degeneration Firewalll

I have devoted a blog mini-treatise specifically to research on lifestyle and dietary supplement interventions that can delay or reverse age-related cognitive decline , memory loss and other age-related forms of neural degeneration such as hearing loss. It is the July 2011 post Age-related cognitive decline: focus on interventions. The cited research stongly supports the firewall suggestions made here.

Lifestyle

Lifestyle habits seem to be very important for maintaining an active and capable brain and nervous system.  Previous advice is all relevant, particularly that related to the immune system.  The advice “Use it or lose it” seems to be applicable when it comes to the brain.  Meeting mental challenges, movement and exercise seem to be essential for maintaining mental agility as well as body flexibility. There is evidence that regular physical exercise contributions to control of blood glucose levels which tend to rise with age and are implicated in hippocampal dysfunction and the onset of dementia and cognitive decline. Avid and regular pursuit of work, travel or a hobby can be helpful.  Keep active.  Close and frequent social interactions with friends and family are also helpful. And don't poison your brain with excess alcohol, toxic or illegal drugs.

Recent research related to brain neurogenesis highlights the importance of this conventional wisdom. The March 2009 issue of Scientific American reports research on what happens to neurons after neurogenesis in rats. Under normal circumstances, thousands of new neurons are generated every day in the dendrate gyrus of the hippocampus. Within a few weeks most of those neurons die if the animal’s life is unremarkable. However, if the animal is confronted with a sufficiently daunting and important learning task and successfully learns something complex and new, then many of the neurons will stay alive. This appears to be particularly applicable to learning that affects future behavior.

There is an intricate set of interrelationships between neurogenesis in the brain, mood stabilization and cognitive capability, age, exercise, mental task involvement, environmental factors such as stress and respect of circadian rhythms including patterns of sleep. The lifestyle patterns and activities suggested above promote neurogenesis. Mental or physical stress inhibits it. Maintaining consistent daily rhythms, mood stabilization, and proper neurogenesis are highly interconnected. For example, it is well known that aberrant daily rhythms may induce bipolar disorder episodes. A key underlying mechanism could be abnormality in hippocampal neurogenesis which is time-of-day dependent. Maintaining a regular daily pattern of activity and sleep is important.

A number of blog entries are relevant to diet in relation to mental states, includiing Diet and cognition, and Warding off Alzheimer's Disease and things in my diet. I believe that care innutrition as well as dietary supplements can play important roles in delaying the onset of late-life dementia and quite possibly in reversing the debilitating effects of such dementias including Alzheimer's disease. There is a great deal of research in these areas which I have covered in three January 2012 blog entries: Dietary factors and dementia - Part 3: plant-derived substances that can make a difference, Dietary factors and dementia - Part 2: possible interventions, and Dietary factors and dementia - Part 1: important recent research.

Supplements for the neurological degeneration firewall

I have already mentioned the capability of acetyl-l-carnitine and alpha lipoic acid to penetrate into the mitochondria and prevent oxidative damage.  This is particularly important in nervous system cells which regenerate very slowly.  Pumping out lipofuscin from nervous system cells using acetyl-l-carnitine and meclofenoxate is also important for the same reason.  Acetyl-l-carnitine also appears to have an ability to protect and increase receptors in the brain that normally decline with age.  Besides removing lipofuscin, meclofenoxate produces DMAE when metabolized in the body, a natural substance found especially in fish and also produced in the human brain.  DMAE, is a precursor to acetylcholine, an essential neurotransmitter.  DMAE offers other benefits as well; for example it alters muscle contraction and is useful for increasing flaccidity and reducing wrinkles and in the facial region.  I take another smart drug called piracetam which has an effect on brain energy metabolism and supports cognitive functioning. I also take meclofenoxate to improve my memory and cognitive capabilities.    Also the hormones I am taking, pregnenalone, DHEA and melatonin, serve to enhance my mental functioning and my ability to be awake and sleep in regular cycles. 

There is significant research establishing that curcumin promotes neurogenesis. This topic is treated comprehensively in the blog entry Neurogenesis, curcumin and longevity.

L-theanine is derived from green tea and crosses the blood-brain barrier. It promotes expression of the neurotransmitter seratonin.  There is evidence that l-theanine is neuroprotective, and that it supports relaxation and  enhances cognitive function.  It appears to decrease the transmission of stimulating neurotransmitters while promoting the transmission of calming neurotransmitters.  There is experimental evidence that l-theanine may be protective against strokes and may protect against the glutamate toxicity associated with Alzheimer’s disease.  There is also evidence that the hormones I take, melatonin, pregnenalone and DHEA,  have important positive neural and immunomodulating effects, as discussed later here. 

L-carnosine, another component of this firewall, has a capability to reduce brain damage due to accumulation of beta-amyloid and possibly due to malondialdehyde or hypochlorite anions, factors in Alzheimer’s disease and other forms of senile dementia. See the blog entry Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation.

Excess homocysteine is associated with cognitive function decline.  To buffer against this I take vitamins B-6, B-12 and folic acid as part of this firewall.

On another front, there is some evidence that excess angiogenesis (origination of blood vessels) is implicated in Alzheimer’s disease as well as in the proliferation of cancers.  Alzheimer’s disease appears to arise through a combination of oxidative damage, inflammation and excess angiogenesis.  Many of the flavinoids recommended in this firewall program work against all three of these causes.  For example, green tea, curcumin, resveratrol and OPC are antioxidants, anti-inflammatories and have anti-angiogenic properties.  Especially in combination, they show promise for prevention of Alzheimer’s disease.  I have already mentioned other components of the firewall against Alzheimer’s disease and senile dementia: protection against DNA damage through use of antioxidants, and immunomodulation through taking hormones.

Resveratrol protects neurons against toxicity induced by beta-amyloid and provides another approach to defense agaainst Alzheimer’s disease.

Ginkgo biloba is another component of this firewall, a substance shown experimentally to enhance neurogenesis though not necessarily mental acuity(ref). It also appears that the levels of metals in the cerebrospinal fluid of Alzheimer’s disease patients is abnormal, for example showing an increased level of mercury. The supplements mentioned previously to control heavy-metal toxicity like l-carnosine and acetyl-l-carnitine are important for neurological health. Also, selenium has been shown to offset the toxicity of serum lead on the hearing function.

Some studies suggest that magnesium, another component of this firewall, can help in reducing the duration and frequency of headaches and improving learning, memory and cognitive skills for aged people.  Apparently, magnesium locks into key brain neural receptors that participate in governing these mental capabilities.

As discussed earlier, there is evidence that mood disorders, bipolar and related diseases may be in part due to insufficient or abnormal neurogenesis. Neurogenesis is also promoted by several substances that are part of the anti-aging firewalls program: the neurosteroids melatonin, DHEA, and pregnenalone. Also, curcumin, resveratrol, Ginkgo bilboa and EPA fish oil according to published studies. Folic acid and the fish oil components DHA and EPA serve together to improve cognitive function and prevent depression, dementia and Alzheimer's disease, one of the mechanisms being the upregulation of neurogenesis(ref).I speculate that several other psycho-active firewall substances like piracetam, meclofenoxate, ginger extract and withania somnifera (ashwagandha) may also promote neurogenesis. I have been able to identify literature references that strongly suggest this speculation but none that experimentally confirm it.

As this discussion indicates, the firewalls provide in-depth defense against age-related cognitive decline and disease. Now, having recently turned 79, I am in an intensely creative period in my life and I believe my brain is working as well as or better than at any earlier time in my life.  I intend to keep it that way for a long time to come.

9. Decline in Hormone Levels Firewall

Lifestyle

Lifestyle is felt to play a major role in maintenance and natural regulation of hormone levels.  Here I would emphasize the role of regular exercise.  On most days I do at least 45 minutes of mildly cardiovascular exercise – yard work, brisk walks in the countryside, swimming or treadmilling.  Regular good sleep, avoidance of too much caffeine or alcohol are also important.  And I believe mental activity is also important – like researching and writing this article.

Supplements for the decline in hormone levels firewall

Since hormones play such an important role in regulating multiple body systems, my approach as been to take supplements to maintain higher levels of some of the most important hormones than would occur naturally at my age.  My objective is to maintain the level of functionality of a healthy 55 year-old.  I do not take HGH or HGH promoters because they can have serious side effects – I tried once  and got a serious case of arthritis.  I do take two precursor “mother” hormones, however: pregnenalone and DHEA.  Pregnenolone converts itself in the body into all other steroid hormones including DHEA, progesterone, estrogen, testosterone and cortisone.  The extent to which it converts into estrogen or testosterone is a function of gender.  Studies show it provides benefits in terms of lessening joint pain, improving cognitive function, enhancing skin condition and helping prevent joint pain.  DHEA is another precursor hormone with natural levels declining with age.  It is depleted by taking certain drugs and by certain disease conditions including AIDS and diabetes.  Research indicates it is useful for treatment of adrenal insufficiency, depression, and SLE (systemic lupus erythematosus).  I also take melatonin for regularity of sleep and for several others of its possible anti-aging benefits, including immune system regulation.  Melatonin appears to be a regulator of the 24-hour circadian rhythm of biochemical, physiological and behavioral processes. I also use melatonin to speed the adoption of my body rhythms when I travel internationally across several time zones.  On the mineral side, magnesium and calcium supplements are very important for maintaining my bone density as natural levels of density-regulating hormones decline. 

Resveratrol is another important firewall substance for protection against age-related bone loss. Resveratrol "enhances proliferation and osteoblastic differentiation in human mesenchymal stem cells" according to one study(ref). According to another research report "In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy -- "(ref) . See also the discussion below regarding curcumin and protection against bone loss.

Hormone levels appear to be implicated in the pathogenesis or prevention of many cancers, particularly breast cancers in women and prostate cancers in men. Melatonin has been shown to be protective against breast cancers. In about half of all prostate cancers, there is a common gene alteration. In the presence of this gene alteration, estrogen-linked signaling helps trigger an aggressive form of the disease. Stinging nettle extract, saw palmetto, selenium, zink, and lycopene are substances in my firewall regime that contribute to control of estrogen, testosterone and other related hormone levels.

With respect to insulin resistance, chromiom piclonate contributes to both weight management and burning-off of extra insulin. Other substances in this firewall that assist in controlling excess insulin are DHEA, fish oil, CoQ10, alpha-lipoic acid, l-carnosine, vitamins C and E, and magnesium. These as well as exercise also contribute to weight management and control of glycation.

Again, the interrelationships among the theories of aging are complex. Most of the lifestyle suggestions as well as firewall substances have pluripotent effects related to several of the theories of aging.

10. Susceptibility to Cancers Firewall

Lifestyle

Most of the critical lifestyle actions have already been covered: minimize x-ray exposure, avoid sources of radioactivity, wear sunscreen, avoid contact with chemicals that induce carcioogenesis like paint removers, avoid foods with carciogenic additives.  Do not smoke and avoid second-hand smoke. Eat a diet with a low glycemic index. Physical activity and regular exercise are also helpful, for example both in prevention of breast cancer and assuring positive health after breast cancer treatment(ref). 

Supplements for the Susceptibility to Cancers Firewall

In this category I recommend a broad-spectrum approach involving different supplements each with different characteristics that fight cancer  All the antioxidants previously mentioned help prevent cancer-inducing mutations.  Vitamin D-3 has multiple cancer-fighting properties as do each of the phytochemical supplements I take.  Resveratrol and curcumin, for example, activate the P53 gene in many strains of cancer cells, leading them to commit apoptosis.  So does Green tea, OPC, lycopene and olive leaf extract.   The genetics-related research evidence for these claims is impressive and growing though I cannot cite it here without losing the untrained reader.[5] The pathways of of operation of these substances can be quite complex. for example, it appears that curcumin acts to control the proliferation of neurogliaoma cells by modulating gene expression related to at least four different pathways: oxidative stress, cell cycle control, and DNA transcription and metabolism.(ref)   A comprehensive review of the actions of curcumin in cancers can be found in the blog entry Curcumin, cancer and longevity.

A cluster of research reports has appeared during the last few years looking at mechanisms through which substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, sage) are cancer-preventative. While these foods have been studied for many years a new focal point has been moving to center stage - study of what these substances are doing in terms of gene expression as a key to understanding their therapeutic value. The blog post Nrf2 and cancer chemoprevention by phytochemicals reviews and provides citations to some of this research and discusses the role of the nuclear factor Nrf2 in phytochemical cancer chemoprevention. The blog entry Back to blueberries lists a number of research publications describing the pathways of action of pterostilbene, a powerful anti-inflammatory substance in blueberries, and describing the anti-cancer properties of this substance.

Omega-3 oils offer other cancer-inhibiting capabilities. Selenium is another substance in the firewall; it has its own mechanisms for inducing apoptotic death of tumor cells.  Magnesium seems also to be useful for reducing the risks of certain cancers, such as colon cancer. Several of the substances in the firewall including curcumin, vitamin D-3, and lycopene have been well researched and show sufficient anti-cancer capabilities that they are being investigated in Phase I and Phase II clinical trials. Astragalus also appears to have anti-tumorigenic potential for certain cancer cell types includong colon cancer(ref).

NF-kappaB cell signaling is deeply implicated in both inflammatory and carcinogenetic processes which have long been known to be intimately related. A host of recent studies illuminate how NF-kB signaling is involved at the heart of inflammation, inflammatory diseases like arthritis, and cancer initiation and progression. As pointed out in the 13th firewall below, thirty-nine of the substances in the combined firewall are NF-kB inhibitors contributing to reduction of inflammation, preventions of cancers and, possibly even, organ renewal.

11. Susceptibility to Cardiovascular Disease Firewall

Lifestyle

Again, most of the critical lifestyle actions have already been covered.  Do regular daily mildly-cardiovascular exercise(ref). But avoid extremes in exercising.  Avoid foods and drinks with a high glycemic index. Maintain your weight within normal ranges.  Monitor and maintain normal blood pressure, preferably under 130/70.  Eat healthily, featuring vegetables, fruits and fish.  Avoid browned or fried foods, foods cooked in trans-fats or saturated fats, fast foods and junk foods in general.    Minimize stress and Type  A behavior.  Again, following a Mediterranean diet can be very helpful. Avoiding environmental toxins is also very important, starting with clean air and clean water. A recent study by Harvard School of Public Health and Brigham Young University(ref) researchers points to the importance of good air quality. It appears that improvements in air quality in the US, particularly in cities, added about five months to life expectancy in the U.S. over twenty years. If you can manage to live where the air quality is good, do so. Otherwise, using a HEPA air filter can help, particularly in the bedroom at night. If your water supply is poor or heavily chlorinated you can also consider installing a high-performance filtering system for your drinking and cooking water, one that can filter out lead and other heavy meals as well as microbes. Avoid drinking liquids that have been frozen or heated in plastic bottles and don't microwave food in plastic containers. And don't drink liquids that have been frozen in plastic containers.

Supplements for the Cardiovascular Disease Firewall

Millions of people have been taking statins like Lipitor as part of a presumed firewall against cardiovascular disease, but I do not take them. Nor do I suggest taking statins for people without a history of heart disease and having a C-reactive protein score in the normal range.  The US population has been convinced by an immense advertising and propaganda campaign to blame cardiovascular diseases almost entirely on the presence of a high level of cholesterol.  There is a multi-billion dollar market for statins to lower cholesterol levels and understandably the drug companies involved want to protect their profits. New research shows that longevity of people without initial cardiovascular problems and with a normal C-reactive protein score taking statins is no longer than longevity of people who do not take them.  The presence of a high cholesterol level is only one factor when cardiovascular  diseases are concerned, and probably not the most important factor.  Coronary artery occlusion can be caused by combinations of 14 known factors, many involving glycation and inflammation.  A high serum level of cholesterol is only one of them.  So, the supplements already mentioned that control glycation and inflammation are important – including the polyphenols, benfotiamine and l-carnosine.  Carnosine also counts being an anti-ischemic agent as among its pluripotent capabilities.

Omega-3 oils are at the heart of this firewall.  Dietary intake of sufficient omega-3 polyunsaturated fatty acids reverses the Omega-3/Omega-6 fatty acid imbalance mentioned previously as well as dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production.  The result includes improved tolerance of ischemia and reperfusion.  Even the crusty anti-supplements American Heart Association now recommends taking Omega-3 oils.  The active components are DHA and EPA and it is important that the supplement capsules taken contain adequate amounts of them.  The risk of heart attack or unstable agina was reduced  62% for every 1.24% increase of EPA and DHA in serum blood level  compared to age-matched controls, according to a recently-published study of over 1,000 patients.   I suggest 1500mg of EPA and 1000mg of DHA twice a day.  

Of course, obesity is a major predictor of many cardiovascular diseases. Resveratrol, curcumin, chromium piclonate, L-theanine, quercetin, Vitamin A, and green tea extract contribute to weight management and reduction of abdominal fat.  Consumption of green tea appears to strongly support the health of circulatory endothelial cells, preventing or delaying the onset of  atherosclerosis.   Green tea and L-theanine also reduce fatty acids in blood serum. 

A number of the plant flavinoids that I have mentioned can contribute significantly to lowering blood pressure,  in turn lowering  risk of stroke, congestive heart failure and other problems.  Research indicates that dark chocolate alone can make an important difference in this regard. In at least one study, taking acetyl-l-carnitine is reported to result in reduction of fat mass and increase in muscle mass, again predictors of cardiovascular health.  There is also evidence that astragalus contributes to improvement of  cardiovascular system health.  This can be seen in clinical measurements associated with angina, congestive heart failure and acute myocardial infarct.

Lycopene is another component in this firewall as is allicin, a garlic extract. Epidemiological studies have shown an inverse relationship between tissue and serum levels of lycopene and mortality from myocardial infraction, coronary heart disease and cardiovascular disease. A recent meta-analysis of 25 systematic studies indicates that garlic extract is as effective in reducing blood pressure as the usual prescription beta-blocker medications given for this purpose.

Magnesium is another pluripotent supplement in the firewall that is useful for preventing cardiovascular diseases and hypertension.  It helps to stabilize blood pressure, prevent arrhythmia, reduce cardiovascular inflammation, and reduce the consequences of congestive heart failure.  Maintaining proper electrolyte (potassium-sodium) balance is also key for proper functioning of the heart as well a number of other systems including muscles, nerves, kidneys, and the digestive track.  Since I get plenty of sodium in my salt intake, I also take a potassium supplement as another component of this firewall.

An excessive level of blood homocysteine is associated with elevated risk of heart attacks and stroke.  These levels may result from inadequate supplies of certain nutrients including vitamins B-6, B-12, and folic acid.  These nutrients are also part of this as well as other firewalls.   Finally, Vitamin D is another important firewall component.  A recent eight-year study of 3,258 men and women  indicates that the higher the blood level of Vitamin D, the less is the chance of dying from heart disease - and the less the chance of dying from a number of other diseases as well. 

12. Telomere Shortening Firewall

Lifestyle

The general rule is to keep your telomeres long  while you have them that way.  This means avoiding excessive or prolonged stress of all kinds be it environmental, physical or psychological. It means avoiding radiation, infections, bug bites, wounds, excessively strenuous exercise and heavily stressful human situations.    Actually some stress such as through regular not overly-stressful exercise might help keep your telomeres long. See the blog entry Stress, exercise and telomere lengths. Positive mental attitude and good relationships can help.  So can all the other firewalls already mentioned.  Be aware that chemotherapy and radiation therapy or personal crises can take years off of your life through telomere shortening. A quite thorough discussion of practical means for keeping telomeres long can be found in the October 2010 blog entry Lifestyle, dietary, and other factors associated with telomere shortening and lengthening. That blog entry also links to earlier blog entries relevant to telomere lengths.

Supplements for the Telomere Shortening Firewall

A study of 586 women reports " -- the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users." Antioxidant regimes and the other firewall supplements already mentioned can help maintain health and minimize undue cell replication resulting in telomere shortening. Shortening may be due to an excess rate of cell duplication or, more directly, to single-strand breaks in the telomeric DNA, both most-frequently resulting from oxidative damage. In metabolic syndrome patients with coronary artery disease an association can be observed in circulating endothelial progenitor cells between oxidative DNA damage and telomere shortening.  Therefore, anti-oxidant measures can be very useful for preventing telomere shortening and disease progress  in such patients. The blog entry Vitamins, supplements and telomerase - upregulation or downregulation? cites research literature references on population studies coupling supplementation with Vitamin E, fish oils, Vitamin D3 and resveratrol with having longer telomeres.   L-carnosine also appears to reduce or even reverse telomere damage and shortening rates, at least in cultured human diploid fibroblasts.  Studies going back to 1994 indicate that Carnosine can delay senescence and promote formation of a more juvenile phenotype in such cultured human fibroblasts, extending the Hayflick limit for reproduction of such cells by up to ten doublings.  I conducted a literature review of l-carnosine a few years back and continue to be impressed by this substance. See the November 2009 Blog entry The curious case of l-carnosine . 

For the author, up until recently the Holy Grail of life extension has been to rejuvenate organs and perhaps whole animals by extending telomere lengths. The idea has been to reset cells and therefore reset organs and entire bodies to an earlier biological state.  Young bodies generally have a vastly greater capacity to handle diseases of old age like cardiovascular problems, cancers Alzheimer's, Parkinson's,diabetes, etc.  Either these diseases are much rarer in young people, or have less serious consequences, or don't occur at all.  Young bodies know how to avoid or get rid of AGEs and lipofuscin and have much more effective antioxidant defences and DNA repair mechanisms than older ones.  The basic concept of life extension through telomere extension is to reset bodies and the organs in them to an earlier biological age, to an age when the body has the capacity to shrug off the diseases of old age.  If this theory of  aging is correct then it relegates most of the previously listed theories of aging to secondary status.  The central anti-aging firewall needed is to reset the body to an earlier age.  The other firewalls in combination might be capable of getting one in a healthy active state to 100 or 115 years of age.  An effective firewall against telomere shortening might get one to 250 to 500 good years of life, so I thought for many years.  Since 1994,  I have been aiming for 240 good years but might extend that target if biotech research moves fast enough.  I waited 14 years for the emergence of a safe and effective telomere-extending technology.

Now there is much more knowledge available about telomeres and a dietary supplement is available that is believed to work to extend telomeres. However, as described above I no longer see telomere extension as being the central key to extraordinary longevity. Over the years there have been no reported small-animal experiments resulting in significantly enhanced longevity due to telomere extension. So, the notion that enhanced telomerase expression can by itself lead to radical life extension in humans remains hypothetical. However, there has been continuing research evidence suggesting that maintaining both telomerase expression and telomere lengths is key in any program for extraordinary longevity. I have also not given up on the concept of resetting cells, organs and bodies to an earlier biological age. Rather, I have expanded my viewpoint to allow this to come about also through other means – such as through addressing two of the theories of aging I added after initially drafting this treatise: Programmed genetic changes and Decline in adult stem cell differentiation,

Achieving longevity through telomere extension is potentially tricky.  One of the key transformations of a normal cell into a cancer cell is turning on the hTERT telomerase gene.  Telomerase does not cause cancers but can cause them to go into high gear.  Telomerase expression plays a role in tumor progression and it appears that the telomerase RNA component Terc is key as to what telomerase does regarding tumorgenesis.  Telomerase-mediated telomere length maintenance could therefore possibly enable certain mutant cells to efficiently move into a fully malignant state, including metastasis.  This is more than a bit scary, a high-stakes game.  Possibly, the telomerase gene shutting down in older adults is an evolutionary defense against cancers.

Earlier versions of this treatise contained a discussion of how telomerase might possibly be activated via suplements which are extracts from astragalus. I continue to see telomeres and telomerase as extremely important topics from a longevity perspective. However, I no longer see taking a telomerase extender like astragenol as likely to be a useful anti-aging intervention. Instead, I believe there is ample research supporting the pursuit of certain conventional-wisdom lifestyle and dietary patterns as ways of keeping telomeres long. My thoughts are expressed in a series of blog entries, particularly The epigenetic regulation of telomeres, Lifestyle, dietary, and other factors associated with telomere shortening and lengthening, and particularly in the October 2010 blog entry Lifestyle, dietary, and other factors associated with telomere shortening and lengthening.

For historical purposes, I have moved the earler discussion of astragulus-based supplements intended to extend telomeres to here.

Going to my blog using this link will reveal a large number of earlier postings relating to telomeres and telomerase expression.

13. Programmed Epigenomic Changes Firewall

Lifestyle

The main thing that can be said here is that the molecular pathways that relate diet, exercise, sleep and social patterns to epigenetic gene regulation have been under intense research scrutiny and are inreasingly being understood. Exercise, sleep patterns, foods and supplements can simultaneously affect multiple biological pathways related to health and longevity such as AMPK, Keap1-Nrf2, NF-kappaB, GH-IGF, the heat shock response pathway (HSR), p53, FOXO and the unfolded protein response pathway (UPR). Further, we are starting to understand how these pathways interact so as to reinforce or inhibit each other. The traditional advice for lifestyle mentioned in earlier sections still pertains. What has been changing has been understanding of how following that advice plays out in terms of epigenomic gene activation pathways. The previously-made suggestions are still valid.

Supplements for the Programmed Epigenomic Changes Firewall

The first theory I mentioned of aging as programmed genetic changes is the telomere shorting one and the firewall against it is described in the previous Section.

The second theory I mentioned, epigenomic changes involving DNA methylation and histone actetylation are of prime importance. A number of supplements in my combined firewalls list act via epigenetic mechanisms and act via the Keap1-Nrf2 pathways to modify gene expression in health-producing ways. The subject is fascinating and complex and I recommend that interested readers look at my some of the multiple blog entries that deal with it including (February 2012) * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects.Human healthspan and lifespan extension?, * Part 2 - foods, phyto-substances and other substances that turn on Nrf2, and * Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension? Also, a great many earlier blog entries are relevant, a sample being * Dietary factors and dementia - Part 3: plant-derived substances that can make a difference, * Dietary factors and dementia - Part 2: possible interventions, * Dietary factors and dementia - Part 1: important recent research, * Focus on phytosubstances - Danshen root - amazing properties of salvia miltiorrhiza Bunge, , * Phytosubstances - focus on cats claw, * Focus on bitter melon, * * Age-related cognitive decline: focus on interventions, * Health and longevity benefits of plant polyphenols - focus on grape seed extract, * Focus on ginger * PQQ - activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, * The epigenetic regulation of telomeres, , * The many faces of folic acid, * Cancer, epigenetics and dietary substances, * JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging.,

The third theory I mentioned of aging as programmed epigenomic changes suggests that at least limited age reversal on the organ level can be achieved by blocking the expression of NF-kappaB. It happens that many of the supplements in the Anti-Aging Firewall regimen identified up to this point powerfully inhibit NF-kappaB cell signaling. In most cases these are substances often classified misleadingly as "antioxidants" that serve to turn on the expression of Nrf2. They serve the dual function of turning on the expression of multiple body antioxidant and stress protection genes and protecting against inflammation by surpressing the expression of NF-kappaB. My research of the literature indicates that significant but different effects on inhibition of NF-kappaB expression and/or binding activity are exercised by each of the anti-aging firewall substances in this table: