Aging And Dementia Links

Aging and dementia has common links, including the mitochondrial α-F1 -ATP synthase (ATP5A), which can be a target for the Alzheimer's disease drug candidate J147.  The mTOR signaling pathway is involved with this; abstract:

Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F1 -ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

More On Mitochondria And Alzheimer's Disease

It has been shown that the stimulation of certain mitochondrial functions can increase the fitness and lifespan of a worm model of Alzheimer's disease and also reduce amyloid aggregation (that has been associated with Alzheimer's disease) in a variety of model systems, including mice. These findings may lead to anti-Alzheimer's therapeutics.  Abstract:

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

"Mutation-Independent" Cancer Therapy: Targeting Mitochondria

By Kelvinsong - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=27715320

Mitochondria are the “powerhouses of the cell” and problems with mitochondria have been associated with cancer.  So, putting stress on mitochondria can mimic the effects of aberrant gene expression to stimulate breast cancer stem cell activity.  This effect can be inhibited by the antibiotic doxycycline, demonstrating that “mutation-independent” cancer therapy approaches can be used against cancer – approaches that target such phenomena such as mitochondrial function and reproduction, or some other aspects of cell phenotype, as opposed to targeting specific gene mutations and the aberrant products of such mutated genes.  Abstract:

Here, we used MCF7 cells as a model system to interrogate how MYC/RAS co-operativity contributes to metabolic flux and stemness in breast cancer cells. We compared the behavior of isogenic MCF7 cell lines transduced with c-Myc or H-Ras (G12V), either individually or in combination. Cancer stem cell (CSC) activity was measured using the mammosphere assay. c-Myc augmented both mammosphere formation and mitochondrial respiration, without any effects on glycolytic flux. In contrast, H-Ras (G12V) synergistically augmented both mammosphere formation and glycolysis, but only in combination with c-Myc, directly demonstrating MYC/RAS co-operativity. As c-Myc is known to exert its effects, in part, by stimulating mitochondrial biogenesis, we next examined the effects of another stimulus known to affect mitochondrial biogenesis, i.e. ROS production. To pharmacologically induce oxidative stress, we used Rotenone (a mitochondrial inhibitor) to target mitochondrial complex I. Treatment with Rotenone showed bi-phasic effects; low-dose Rotenone (1 to 2.5 nM) elevated mammosphere formation, while higher doses (10 to 100 nM) were inhibitory. Importantly, the stimulatory effects of Rotenone on CSC propagation were blocked using a mitochondrial-specific anti-oxidant, namely Mito-tempo. Thus, "mild" mitochondrial oxidative stress, originating at Complex I, was sufficient to pheno-copy the effects of c-Myc, effectively promoting CSC propagation. To validate the idea that mitochondrial biogenesis is required to stimulate CSC propagation, we employed Doxycycline, a well-established inhibitor of mitochondrial protein translation. Treatment with Doxycycline was indeed sufficient to block the stimulatory effects of H-Ras (G12V), c-Myc, and Rotenone on CSC propagation. As such, Doxycycline provides a strong rationale for designing new therapeutics to target mitochondrial biogenesis, suggesting a new "mutation-independent" approach to cancer therapy. In support of this notion, most currently successful anti-cancer agents therapeutically target "cell phenotypes", such as increased cell proliferation, rather than specific genetic mutations. Remarkably, we demonstrated that Doxycycline inhibits the effects of diverse oncogenic stimuli, of both i) genetic (MYC/RAS) and ii) environmental (Rotenone) origins. Finally, we discuss the advantages of our "Proteomics-to-Genomics (PTG)" approach for in silico validation of new biomarkers and novel drug targets. In this context, we developed a new Myc-based Mito-Signature consisting of 3 mitochondrial genes (HSPD1; COX5B; TIMM44) for effectively predicting tumor recurrence (HR=4.69; p=2.4e-08) and distant metastasis (HR=4.94; p=2.8e-07), in ER(+) in breast cancer patients. This gene signature could serve as a new companion diagnostic for the early prediction of treatment failure in patients receiving hormonal therapy.

Do Bacteria Run The Show?

http://www.hypothesisjournal.com/wp-content/uploads/2016/11/HJ479_Fig1.png

Are humans merely vehicles for accomplishing the objectives of bacteria (and life in general) to spread itself?  Here is a hypothesis paper that suggests that prokaryotes (e.g., bacteria) have followed a two-pronged strategy to shape higher eukaryotes (e.g., humans) to achieve the end of spreading bacteria worldwide and spacewide: via the mitochondria (derived from an ancient prokaryote and symbiosis) and the microbiome. Of course, we are not talking about conscious strategies; there is no anthropomorphizing of bacteria!  But the end result of selection and the general tendency of life to find ways of spreading has led to this conclusion. Abstract:

Beyond considering that humans are not just composed of eukaryotic cells but also of a huge number of microbes playing pivotal roles in the overall organism functioning, in this article it is additionally suggested to look at eukaryotic cells as a kind of evolved community of bacteria-derived individuals. Mitochondria are fundamental organelles for energy production, but also for driving cell fate. Although it is perfectly established that mitochondria are phylogenetically linked to bacteria, with theories suggesting they survived in a symbiotic parasitism within an ancestral eukaryotic cell, we alternatively encourage their consideration as the main orchestrators of eukaryogenesis. Bacteria gradually evolved into mitochondria, while the social interrelationship and architecture of a prokaryotic community transformed into eukaryotic cells. Last but not least, given the role of bacteria on Panspermia, and by converging mitochondrion and microbiome potential to respectively modulate cell and whole organism functioning, we wonder whether superior animals and in particular humans might be so far the most evolved product coming from two main bacterial socio-evolutive strategies engaged in an attempt to endure living matter expansion.

Conclusion:

In conclusion, independently of whether humans are simply a “clothing”, a subject hijacked by the host or the final refined product resulting from the convergence of two different microbial socio-evolutive strategies, it might be worth giving more consideration to the fact that the ultimate “aim” of bio-evolution is not humans but the perpetuation of living matter. Humans could be just a piece of the whole biosphere puzzle and might not be necessarily the most important nor the end result. We may simply be the most sophisticated living matter approach, intentional or not, engaged in an attempt to endure a goal of bioevolution that is panspermia (38-44,113-116).

Mitochondria And Aging: Fruit Flies...And Perhaps Humans As Well

By André Karwath aka Aka - Own work, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=227170

The mitochondria are the “powerhouses” of the cell, and problems with mitochondria and mitochondrial function have been associated with a number of diseases and disorders. Increased levels of dysfunctional mitochondria have been linked to aging, and this study linked here shows that “middle-aged” Drosophila (fruit flies) tend to have more elongated, dysfunctional mitochondria. Upregulation if a gene called Drp-1 promotes fission of those aberrant mitochondria, which in turn enhances mitophagy (in simple terms: cellular “clean-up” of the dysfunctional mitochondria) and enhanced mitochondrial function.  This in turn has anti-aging effects in the flies. Now, the objective here is not to improve the health of aging fruit flies (which may or may not be a worthy goal on its own, depending on your perspective), but to apply these findings to the human case, and to see how further investigation into these findings can inform us about ant-aging strategies in humans. This is the basic science-human health link on full display.  Abstract:

The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1-a Dynamin-related protein that promotes mitochondrial fission-in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife. Mitochondrial fission and fusion are important mechanisms to maintain mitochondrial function. Here, the authors report that middle-aged flies have more elongated, or 'hyper-fused' mitochondria, and show that induction of mitochondrial fission in midlife, but not in early life, extends the health and life of flies.

"Divide and conquer" - does it work in cancer care

Fotogeniss -

Philip-ii-of-macedon

"Divide and conquer" may have worked for Philip II of Macedon; however, is it an effective strategy in understanding cancer development and providing cancer care?    

Have you seen the talk by Dr. Gary Fettke, "Nutrition and Cancer - Time to Rethink"? The talk leads to the conclusion that cancer is a disease of our metabolism. The chromosomal changes, including any gene mutations, seem to be bystanders in the unfolding madness of cancer development.

However, recent research indicates that all cancer cell changes (mutations and metabolic changes), the immediate environment of the cancer cells (influenced by external environmental and internal factors), and the metabolism at the organism level are interconnected, and contribute to the neoplastic growth.

It is not any single element, it is rather the congregation of factors that allows for the abnormality of cancer to emerge, persist, and eventually kill.

We should be mindful of the perils of reductionism in science and cancer prevention/treatment, and try to adopt a holistic view on cancer. Here are the precise definitions of the two approaches:

Reductionism,
the practice of analyzing and describing a complex phenomenon in terms of simpler, more fundamental phenomena...

versus...

Holism,
the theory that parts of a whole are in intimate interconnection, such that they cannot exist independently of the whole, or cannot be understood without reference to the whole...

For more examples on misleading reductionism see here.



ACTIONABLES:
Yes, we should be aware of not only what we eat but how we eat it.

Yes, we should stop drinking to death, and I am not even referring to drinking alcohol.

Yes, we should learn how to cook for ourselves, since the food industry is force-feeding us with loads of sugar.

Yes, you should educate yourself, and not rely on your doctors and mainstream media to do so.

Yes, all of us should be aware that it is easier to deal with a just-born, immature troublemaker than a fully established, mature enemy; in other words, cancer prevention is more effective than cancer treatment.

Yes, we should try to integrate mainstream and alternative approaches to cancer care.

And yes, for all of you cancer researchers and enthusiasts: analyzing a phenomenon by breaking it down to its elements/building blocks and addressing only a single element is not going to bring a success. Cancer prevention and treatment need to address all aspects of the cancer development.