Inflammation, NAD+, and the mitochondria theory of Anti-Aging

Are We Coming Closer to Eating the Holy Grail of Anti-Aging?

In the late 1940s, Denham Harman PhD, an accomplished chemist, became so fascinated with the idea of finding a cure to ageing that he decided to go back to school and study medicine.

In 1953, while still an intern at Berkeley in California, he proposed a radical new theory called the ‘the free radical theory of ageing’. [i] In this theory, he declared that ageing is caused by reactive oxygen species accumulating within cells.

Denham then noticed that it wasn’t simply the accumulation of reactive oxygen species that affected lifespan, but the damage these reactive oxygen species were inflicting on mitochondria.

So, he modified his theory and gave it a new name: ‘the mitochondrial theory of ageing’. Harman changed the course of anti-ageing research forever.

What are reactive oxygen species?

Mitochondria are energy ‘factories’ within cells. They produce ‘packages’ of energy in the form of the molecule ‘ATP’.

In the process of energy production, single electrons escape from the ‘factory line’ and react with oxygen molecules to form free radicals such as peroxide and superoxide.

These free radicals react with everything and can wreak havoc, this is why they are called ‘reactive oxygen species’. Excessive levels of these reactive oxygen species cause damage to the mitochondria themselves.

They can be ‘mopped up’ by anti-oxidants and mitochondria usually contain anti-oxidants that do this but these may decline in number, over time and with age.

As a result, high levels of reactive oxygen species start to accumulate and cause mitochondrial damage.

Dysfunctional mitochondria can no longer produce enough energy and ‘starving’ cells may degenerate and die.

Brain cells are extremely dependent on their mitochondria for energy and most diseases of old age seem to affect the nervous system, giving credibility to Denham’s theory.

In 1999, another anti-ageing expert, Professor Vladimir Skulachev of Moscow State University, proposed a similar theory on ageing which he calls ‘Phenoptosis’.[ii]

In this theory, mitochondrial death from reactive oxygen species leads first to cell death, then organ death and that then kills the whole organism.

The bottom line of these theories is if we want to live longer, we need to look after our mitochondria.

Anti-oxidant advice

The advice universally given out over the past few decades where we have been told to eat plenty of fruit, chocolate, tea and various other things because they all contain anti-oxidants, is based on these theories.

If we eat anti-oxidants, we can prevent our mitochondria from being damaged by excessive reactive oxygen species. The problem is that eating more anti-oxidants doesn’t seem to have much of an effect on longevity, as some studies have shown.[iii]

One reason may be that the anti-oxidants we eat may not actually reach their target and enter into the mitochondria that need them.

Inflammation turns mitochondria into toxic factories that wreak havoc.

Macrophages are a type of white blood cell  whose normal role is to digest cellular debris and foreign substances. These biological dustbins maraud within and between cells throughout the body, destroying pathogens as they roam.  Normally, this is a good thing.  But they are able to reek havoc  with mitochondria, the cells power plants, if they get out of control.

Mitochondria stop producing energy

http://www.cell.com/cell/fulltext/S0092-8674(16)31162-X

This articles shows how macrophages signal mitochondria to switch from producing ATP (the cells energy source)  by normal oxidative phosphorylation  to glycolysis.  The end product of the glycolysis is ROS that are pro-inflammatory and can be toxic to surrounding cells.

“Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production.”

(Research article that also describes this process – http://www.medicalnewstoday.com/articles/313090.php)

 

 

to produce  Reactive Oxygen Species (ROS).  ROS such as Nitric oxide, superoxide and peroxynitrite induce inflammation and at higher levels damage cells, and are implicated in chronic disease (r) .  Anti-Oxidants are often taken in hopes of combatting these ROS and lowering inflammation, but are often like putting a finger in a leaking dike.

https://www.nature.com/articles/srep33249

This article about newly elevated role of inflammation in neurological disease like MS.

“Increasing clinical, imaging and biopsy evidence show that inflammation also plays a major role3,4, Indeed, a biopsy study in patients with MS concluded that: “Inflammation alone may be sufficient to cause significant clinical deficits without demyelination5. However, the mechanism by which inflammation causes loss of function remains unresolved, although roles for cytokines6, reactive oxygen species and nitric oxide7,8,9 have been proposed. Some of these factors can impair mitochondrial function10, and increasing evidence points to an energy deficit as a major feature of the brain and spinal cord in multiple sclerosis (MS) e.g. refs 1112131415 implicating an energy deficit in the pathophysiology of the functional deficit.

Our findings reveal profound changes in mitochondrial function that parallel the equally profound changes in neurological function. Loss of mitochondrial function at the start of disease expression was accompanied by the increased expression of a key astrocytic glycolytic enzyme.

These data place mitochondrial dysfunction at the centre of the pathophysiology of demyelinating disease of the CNS.”

 

ROS impair mitochondrial function

“The mitochondrial deficits described above were accompanied by an increase in astrocytic PFK2 expression, consistent with a shift from oxidative to glycolytic ATP production in these cells…threshold was breached where ATP supply was no longer sufficient to match metabolic demand…”

“The cause of the mitochondrial dysfunction remains unclear, although roles for hypoxia, superoxide and nitric oxide are implicated by the current and other studies…….Nitric oxide, superoxide and peroxynitrite have also been implicated as responsible for the mitochondrial dysfunction apparent as early as three days after immunisation in excised tissue23, and we have confirmed the mitochondrial dysfunction at early days in vivo (data not shown), a time when inflammatory cells are very few in number, if present.”

“It is difficult from our findings to determine the sequence of events between the onset of mitochondrial depolarisation and the arrival of any inflammatory cells within the spinal cord. However, it is noticeable that the mitochondrial dysfunction in EAE started before the arrival of many inflammatory cells”

In summary, the current findings focus attention on mitochondrial dysfunction and energy insufficiency as a major cause of neurological deficits in neuroinflammatory disease

 

 

Excess Blood Glucose Fuels Inflammatory Fires

(This section from Lifeextension.com)

When glucose is properly utilized, our cells produce energy efficiently. As cellular sensitivity to insulindiminishes, excess glucose accumulates in our bloodstream. Like spilled gasoline, excess blood glucose creates a highly combustible environment from which oxidative and inflammatory fires chronically erupt.

Excess glucose not used for energy production converts to triglycerides that are either stored as unwanted body fat or accumulate in the blood where they contribute to the formation of atherosclerotic plaque.

As an aging human, you face a daily onslaught of excess glucose that poses a grave risk to your health and longevity. Surplus glucose relentlessly reacts with your body’s proteins, causing damaging glycation reactions while fueling the fires of chronic inflammation and inciting the production of destructive free radicals (Basta 2004; Uribarri 2005; Toma 2009).

Avert Glycation and Inflammation by Controlling Glucose Levels with Green Coffee Extract 

Unroasted coffee beans, once purified and standardized, produce high levels of chlorogenic acid and other beneficial polyphenols that can suppress excess blood glucose levels. Human clinical trials support the role of chlorogenic acid-rich green coffee bean extract in promoting healthy blood sugar control and reducing disease risk.

Scientists have discovered that chlorogenic acid found abundantly in green coffee bean extractinhibits the enzyme glucose-6-phosphatase that triggers new glucose formation and glucose release by the liver (Henry-Vitrac 2010; Andrade-Cetto 2010). Glucose-6-phosphatase is involved in dangerous postprandial (after-meal) spikes in blood sugar.

In another significant mechanism, chlorogenic acid increases the signal protein for insulin receptors in liver cells (Rodriguez de Sotillo 2006). That has the effect of increasing insulin sensitivity, which in turn drives down blood sugar levels.

In a clinical trial, 56 healthy volunteers were challenged with an oral glucose tolerance test before and after a supplemental dose of green coffee extract. The oral glucose tolerance test is a standardized way of measuring a person’s after-meal blood sugar response. In subjects not taking green coffee bean extract, the oral glucose tolerance test showed the expected rise of blood sugar to an average of 144 mg/dL after a 30 minute period. But in subjects who had taken 200 mg of the green coffee bean extract,that sugar spike was significantly reduced, to just 124 mg/dL—a 14% decrease (Nagendran 2011). When a higher dose (400 mg) of green coffee bean extract was supplemented, there was an even greater average reduction in blood sugar—up to nearly 28% at one hour.

Ensuring that fasting glucose levels stay between 70 and 85 mg/dL, and that two hour post-meal glucose levels remain under 125 mg/dL can help combat chronic inflammation.

Conventional Medicine Typically Overlooks Chronic Inflammation

Chronic inflammation or para-inflammation is generally not treated on its own by mainstream physicians. Interventions in conventional medicine are usually only undertaken when the inflammation occurs in association with another medical condition (such as arthritis).

Currently, conventional preventive medical approaches to inflammation are limited to the use of CRP to predict cardiovascular disease in high-risk subjects, and the prophylactic use of drugs like aspirin to inhibit the inflammatory cascade linked to thrombosis (uncontrolled blood clotting).

Indeed, the potentially asymptomatic nature of low grade inflammation is such that elevations of pro-inflammatory cytokines may progress undetected for some time, only being discovered after they have had time to cause enough cellular damage to produce disease symptoms.

As future studies solidify the association between inflammatory mediators and different diseases, early detection of cytokine aberrations and anti-inflammatory therapy to reduce disease risk may gain more mainstream acceptance

References:

[i] Harman D. “Aging: a theory based on free radical and radiation chemistry”. Journal of Gerontology1956, 11 (3): 298–300.

[ii] Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR, Obukhova LA, Pasyukova EG, Pisarenko OI, Roginsky VA, Ruuge EK, Senin II, Severina II, Skulachev MV, Spivak IM, Tashlitsky VN, Tkachuk VA, Vyssokikh MY, Yaguzhinsky LS, Zorov DB. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta. 2009 May;1787(5):437-61.

[iii] Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007, 297:842–857.

[iv] Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006;60:223–35.

[v] Jarrett SG, Milder JB, Liang LP, Patel M. The ketogenic diet increases mito- chondrial glutathione levels. J Neurochem 2008;106:1044–51.

[vi] Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. The ketogenic diet increases mitochondrial uncoupling protein levels and activi- ty. Ann Neurol 2004;55:576–80.

[vii] Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL: D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA 2000, 97:5440-5444.

[viii] Massieu L, Haces ML, Montiel T, Hernandez-Fonseca K. Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition. Neuroscience 2003;120:365–78.

[ix] Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate alzheimer’s disease: A randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 2009; 6: 31.

[x] T.B.VanItallie,C.Nonas,A.DiRocco,K.Boyar,K.Hyams,and S. B. Heymsfield, “Treatment of Parkinson disease with diet- induced hyperketonemia: a feasibility study,” Neurology, vol. 64, no. 4, pp. 728–730, 2005.

[xi] Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, Dunn CA, Singh N, Veith S, Hasan-Olive MM, Mangerich A, Wilson MA, Mattson MP, Bergersen LH, Cogger VC, Warren A, Le Couteur DG, Moaddel R, Wilson DM 3rd, Croteau DL, de  Cabo R, Bohr VA. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 2014 Nov 4;20(5):840-55.

[xii] Pérez-Guisado J, Muñoz-Serrano A. A pilot study of the Spanish Ketogenic Mediterranean Diet: an effective therapy for the metabolic syndrome. J Med Food.  2011 Jul-Aug;14(7-8):681-7.

[xiii] DiNicolantonio JJ, Lucan SC, O’Keefe JH. The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease. Prog Cardiovasc Dis. 2015 Nov 13. pii: S0033-0620(15)30025-6.