In this yet another sneak peek draft as part of the parent manuscript rewrite I hereby purvey a research-driven passage upon question specifically reserved for the Ketogenic + Intermittent Fasting Chapter. Just like any other sneak peek(s) drafts ~ these are simply a preview or a work-in-progress chapter previews, as part of my extensive parent manuscript rewrite, and consequently, its entire rebrand progress. This will effectively serve as public "pilot" series of feature article/s to accompany both the completion of re-brand and entire re-writing of this entire concept initiative

Strictly WIP. 

Live-It-Forward, AW.

"What are the mechanistic implications behind Intermittent Fasting?"

Beyond what is usually discussed amidst mainstream media, here we are directly referring to what is still recognised as common amidst nutritional science circles, albeit slightly technical. As one expects and anticipates, there are just far too many effects that are quite frankly, impossible to condense into one passage, alone. Hence, only the more impactful change/s are discussed here.

1. Activates / upregulates AMPK.
2. Downregulates / suppresses MTOR (“Mammalian Target of Rapamycin”) gene and/or protein defined as two complexes ~  MtorC #1 and #2.
3. Activates / upregulates SIRTUIN(s) Genes.
4. Activates / upregulates the SOD or Super Oxide Dismutase systems.
5. Other genes ~ various outcomes downregulation and upregulation over 80% of the human genome.

Readers are encouraged to further their own research reading, at their own end.    

1/4 Activates / upregulates AMPK

AMPK or known as Adenosine Monophosphate-activated Protein Kinase, is famously proclaimed as the “master regulator” in all metabolism as well as  primary sensor of existing energy balance / substrate  availability. From its Biochemistry logistics, AMPK is triggered by a pre-cursor protein known as LKB1; thus constituting to what is known as the “LKB1-AMPK pathway”. AMPK activation appears to be well established by any event that compels an energy expenditure, or in technical terms - any even  that provokes a rise of AMP (Adenosine Monophosphate) over ATP (Adenosine Triphosphate) in the ETC / Electron Transport Chain. In other words, anything that compels an exercise state, fasting state and/or by select intake of specific pharmaceutical drug ~ Metformin, in particular.

AMPK primarily regulates lipolysis, glucose utilisation (especially during exercise), protein and lipid synthesis particularly that of oxidising existing Malonyl COA reservoire  (as a brief reminder one of the many foundational beginning(s) to Ketogenesis), and a regulator to both glycogen storage and their breakdown processes (Richter EA & Ruderman NB 2009).  AMPK has an antagonistic relation with Leptin, as there appears to be mechanistic evidence that Leptin may inhibit AMPK activity in the hypothalamus, and consequently and as briefly mentioned in our previous chapter ~ Leptin itself also contribute, as one of the nine (9)  neurotransmitter(s) involved towards satiety signalling. 

As mentioned, it is a generally agreed view that AMPK is raised during intermittent fasting (Bujak AL et al. (2015)<Endnote>. However to date, and by This Author’s (AW) awareness of clinical trials and studies (at least on humans) thus far there may yet be a number of literature(s) suggesting a contrasting view. One trial (Wijngaarden MA et al. 2013)<Endnote> compared 12 lean and 14 obese subjects subjected to 48 hour prolonged fasting, and that AMPK activation seems to be activated only amongst the obese, yet not in the lean subjects. Provocative as it may sound, AMPK may yet represent only one of many other mediator(s) responsible for the elusive findings amidst research topics of intermittent fasting; that ultimately warrants more research and reading.     

2/4 Downregulates / suppresses MTOR

MTOR activation has been implicated with many co-morbidities  (Diabetes, Cancer, Alzheimer’s and CVD) , as suggested by current research   (Saxton, AR & Sabatini MD, 2017)<Endnote>.  MTOR is technically defined as an  “Antagonistic Pleiotropic” gene ~ which refers to a hypothesis  amongst field of Epigenetics as firstly coined by American evolutionary Biologist George C. Williams in 1957 ~suggesting that activation of certain genes, MTOR chiefly among the included that  favour anabolism(s) ~ are undoubtedly crucial during youthful years of life, yet  appears to be detrimental, at later year(s) as its prolonged activation paradoxically correlates with neurodegenerative diseases as well as cancer (Schemisser & Parker JA 2019)<Endnote>. During youth, one would indeed advocate for a much higher MTOR genetic expression, alongside other(s) namely IGF-1 ~ all for building a crucially and inarguably essential foundation for both resilient physiology and psychology ~ through  muscle mass, steroid hormones, reproductive fitness, to name a few. However if remaining elevated at a later life, are reportedly associated with harmful co-morbidities, particularly towards Neurodegeneration. 

Ketone metabolism including that of intermittent fasting appears to be thus far mechanistically related at inhibiting mTOR through de-phosphorylation  (Willemse L et al. 2023).

3 & 4/4 ~ Upregulates Sirtuin + Superoxide dismutase Systems

Sirtuin(s) represent a family of genes and proteins most correlated with longevity and low inflammation; both mechanistically proposed thus far by its ROS / reactive oxygen species inhibition in the mitochondria through upregulating various Superoxide Dismutase(s), the most studied of which is the Manganese Super Oxide Dismutase (“MnSOD”). 

To briefly enlighten, but grossly summarised here for lay explanation ~ Superoxide Dismutase(s) [“SOD’s”] are widely classified as “detoxifying” defense systems, each categorised as according to the three  most common “catalytic” metal(s) that each system relied on, for its activation  ~ Zinc (Zn), Copper (Cu),  Manganese (Mn) (Fukai T & Fukai Ushio M. 2011).  Each system is tasked to handle, and mitigate, should in the event of superoxide(s) (Oxygen) production usually in contexts of prolonged inflammation and/or stress remains uncontained. Dismutase systems are crucial therefore to ably withstand and safely detoxify all oxidation processes, before such inevitably exerts DNA damages and ultimately determine both the  health and resiliency of overall organic tissues. A reduction in these MnSOD activity alone has been correlated with an increased risk for DNA damage and consequently ~ cancer, as suggested by a pool of studies that are mechanistic, model-based (mice) and observational perspective(s) (Remmen VH et al. 2003).

To  date, there are seven (7) currently known Sirtuin(s), and chiefly among them most appealing to longevity are  Sirtuin numbers #1 and #3 that are thought to be the most impacted by fasting state and caloric restriction. Sirtuin #3 appears to be responsible for the activation of Super Oxide Dismutase, as briefly outlined above. Technically defined as “Class 3 Histone Deacetylase”  (Zhu Y et al. 2013)<Endnote> Sirtuin(s) rely on existing NAD+ reservoir for activation, which as readers may know from our Biochemistry Basic chapter ~ derives from adequate Vitamin B3 / niacinamide / NR status. 

Other (downregulates & upregulations) 80% of the human genome

One reference (Panda, S. 2023) proclaims that “thousand(s)” of genes residing in the brain alone are affected. Obviously outlining all of them is impractical, given their complexity. Hence the following illustrated diagram <censored for drafting purpose> propose just a few of these down(s) as well as up(s) ~ regulation of numerous genetic expressions. 

In addition, the numerous neurotransmitters involved in hunger and satiety are as one expects - affected. An entire chapter on overviewing nine (9) commonly affected protein(s) expressed during starvation, hunger and satiety signalling are discussed previously in our Chapter Hunger & Satiety.

Suffice to say, Intermittent Fasting as a topic remains a fervent interest, deservedly as one argue ~ from this day, and likely all the way for year(s) into the future. 

Thus concludes yet another draft Sneak Peek draft mini (unallocated at present) chapter as part of my manuscript major rewriting. Comment your thoughts and/or feedbacks down below. Live-It-Forward, AW.