May 2, 2016

10 responses to “Hacking Aging”

Posted by in categories: biotech/medical, law, life extension, mathematics

What would you say if I told you that aging happens not because of accumulation of stresses, but rather because of the intrinsic properties of the gene network of the organism? I’m guessing you’d be like: surprised .

So, here’s the deal. My biohacker friends led by Peter Fedichev and Sergey Filonov in collaboration with my old friend and the longevity record holder Robert Shmookler Reis published a very cool paper. They proposed a way to quantitatively describe the two types of aging – negligible senescence and normal aging. We all know that some animals just don’t care about time passing by. Their mortality doesn’t increase with age. Such negligibly senescent species include the notorious naked mole rat and a bunch of other critters like certain turtles and clams to name a few. So the paper explains what it is exactly that makes these animals age so slowly – it’s the stability of their gene networks.

What does network stability mean then? Well, it’s actually pretty straightforward – if the DNA repair mechanisms are very efficient and the connectivity of the network is low enough, then this network is stable. So, normally aging species, such as ourselves, have unstable networks. This is a major bummer by all means. But! There is a way to overcome this problem, according to the proposed math model.

The model very generally describes what happens with a gene network over time – the majority of the genes are actually working perfectly, but a small number doesn’t. There are repair mechanisms that take care of that. Also, there are mechanisms that take care of defected proteins like heat shock proteins, etc. Put together all of this in an equasion and solve it, and bam! here’s an equasion that gives you the Gompertz law for all species that have normal aging, and a time independent constant for the negligibly senescent ones.

What’s the difference between those two aging regimes? The model suggests it’s the right combination of DNA repair efficiency and the combined efficiency of proteolysis and heat shock response systems, mediating degradation and refolding of misfolded proteins. So, it’s not the accumulation of damages that is responsible for aging, but rather the properties of the gene network itself. The good news is that even we are playing with a terrible hand at first, there is a chance we can still win by changing the features of our network and making it stable. For example, by optimizing misfolded protein response or DNA repair.

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  1. Lydia Fucsko says:

    ‘Hacking Aging’ is an excellent and thought provoking paper that is a refreshingly accessible read!

  2. Angelo Napolitano says:

    Sensual meditation helps maintain the neural pathways.

  3. cacarr says:

    I fail to see how these ideas are mutually exclusive.

    You could say that a cars fail to function owing to an intrinsic property of its human maintenance system — but the failure is more immediately a result of accumulated damage.

  4. Neville says:

    I would say that that one should look a little further upstream:
    Why the DNA and mtDNA damage and misfolded proteins with age?

    My research all points to an increase in inflammation, mainly due to AGE etc build up and an aging gut with ever more of the wrong bacteria in it.

    …Post-translational modifications are known to influence protein structure and function. Some of these modifications might affect proteins in detrimental ways and lead to their misfolding and accumulation. Reducing sugars play important roles in modifying proteins, forming advanced glycation end-products (AGEs) in a non-enzymatic process named glycation. Several proteins linked to neurodegenerative diseases, such as amyloid beta, tau, prions and transthyretin, were found to be glycated in patients…

    …Protein glycation due to hyperglycemia resulting in misfolding and aggregation, which is known as one of the most important reasons of diabetes complications…MB-92 showed the greatest potential for inhibition of glycation and oxidation products…and to control protein glycation, misfolding and aggregation…

    Glycation is the reaction of a reducing sugar with proteins and lipids, resulting in myriads of glycation products, protein modifications, cross-linking, and oxidative stress. Glycation reactions are also elevated during metabolic dysfunction such as in Alzheimer’s disease (AD) and Down’s syndrome. These reactions increase the misfolding of the proteins such as tau and amyloid-β (Aβ), and colocalize with amyloid plaques…AGE colocalized with amyloid plaques. In summary, we demonstrate the glycation of Aβ and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and Aβ misfolding…

    Metals like iron etc catalyse and thus greatly speed up the the formation of AGEs.
    Due to the slow turnover of the ECM the rate of formation of AGE soon outstrips the rate at which they are removed from the body.
    The lack of stem cell activity is related, in that the the buildup of extra/intracellular junk blocks the signal to turn into new brain, liver etc cells.

    Some examples of what happens when we go of the source and these metal are removed:

    Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.

    The novel multifunctional brain permeable iron, chelator M30…was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis…

    chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1α protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice.…

    M30 differentially induced HIF-1α-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner…

    …M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3β (GSK-3β). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.
    LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy…and was a more potent metal chelator than pyridoxamine and aminoguanidine…

    …LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation…
    The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation……8;p=765347

    Ninety Percent Reduction in Cancer Mortality after Chelation Therapy With EDTA…with-edta/

    Tiron is able to chelate iron inside the mitochondria, giving 100% protection against UV.
    In this study UV caused the free iron, but iron buildup is a known problem.…tioxidant/

    Chelation therapy/glycation research seems to be actively discouraged…?!!!

    Lastly; Low dose Nilotinib looks to be the best therapy currently available for:
    Clearing misfolded proteins.
    Preventing amyloid secretion into the extracellular space between neurons.
    Facilitating the mitophagy of old, sickly mitochondria.