Does DSIP prevent/decrease lipofuscin accumulation? Where to start?

My first introduction to lipofuscin was actually TAing a course at the University of Vermont (BCOR103) in which students were viewing aged C. elegans by the fluorescent lipofuscins that accumulated in the adults. I knew about Piracetam before then but I hadn’t really made the connection with lipofuscin.

Lipofuscins are described as products of oxidation of unsaturated fatty acids that can result from membrane damage and cross-linked proteins damaged by oxidation [Terman & Brunk, 2004]. It’s known to accumulate during aging as these products can’t be degraded and removed from the cell. Oxidative stress is known to increase lipofuscin accumulation. Although lipofusin accumulation has been implicated in a number of pathologies (neurodegeneration being a major one) one of the most researched has been its presence in age-related macular degeneration.

Macular degeneration results from deterioration of the central area of the retina (the macula). HMM….THE RETINA, EH? WEIRD. PRACTICALLY ALL THE STUDIES INVOLVING DSIP THAT AREN’T ABOUT DELTA SLEEP ARE ABOUT RETINAL REGENERATION [Ex. Kresyun, 2014]. WEIRD.

Anyway. It is pretty clear that I suspect that DSIP is involved in clearing lipofuscin, in part due to studies suggesting effects countering oxidative damage [Bondarenko, et al., 2001; Bondarenko, et al., 2014; Belykh, et al., 2015; Kutilin, et al., 2014]. Oh yeah, I learned a new thing today. DSIP is also known as deltalycyn.

To really start thinking about this, though, I have to start thinking about areas where there is more information. Clearly, research on DSIP is lacking, but Piracetam has gotten a little more attention and has been shown to decrease lipofusin [Paula-Barbosa, et al., 1991; Brandao, et al., 1995; Riga & Riga, 1995]. Really, there is enough ‘good stuff’ regarding Piracetam that it’s a challenge to know where to start.

There are a few studies that are starting to suggest mechanisms for lipofuscin removal [Riga, et al., 2006]. I would suppose that the most appropriate way to start might be to compare/contrast the effects of Piracetam & DSIP while describing everything that is known about the removal of lipofuscin. So, I guess that is my plan. I think I’ll start with describing the removal of lipofuscin.

This blog post is essentially just to provide a list of resources. My next post will be a more thorough evaluation of some of the studies suggesting methods of removal of lipofuscin.

References:

Belykh, A.E.; Bobyntsev, II; Kryukov, A.A.; Dudka, V.T. [the influence of delta sleep-inducing peptide on functional state of rats hepatocytes in foot-shock stress]. Ross. Fiziol. Zh. Im. I M Sechenova 2015, 101, 700-707.

Brandao, F.; Paula-Barbosa, M.M.; Cadete-Leite, A. Piracetam impedes hippocampal neuronal loss during withdrawal after chronic alcohol intake. Alcohol 1995, 12, 279-288.

Bondarenko, T.I.; Milyutina, N.P.; Shustanova, T.A.; Mikhaleva, II. The effects of delta sleep-inducing peptide on the intensity of lipid peroxidation and xanthine oxidase activity in rat tissues during cold stress. Neurosci. Behav. Physiol. 2001, 31, 83-86.

Bondarenko, T.I.; Kutilin, D.S.; Mikhaleva, II. [rat tissues antioxidant status correction by peptide delta sleep during physiological aging of the organism]. Adv Gerontol 2014,

Paula-Barbosa, M.M.; Brandao, F.; Pinho, M.C.; Andrade, J.P.; Madeira, M.D.; Cadete-Leite, A. The effects of piracetam on lipofuscin of the rat cerebellar and hippocampal neurons after long-term alcohol treatment and withdrawal: A quantitative study. Alcohol. Clin. Exp. Res. 1991, 15, 834-838.

Terman, A.; Brunk, U.T. Lipofuscin. Int. J. Biochem. Cell Biol. 2004, 36, 1400-1404.

Kresyun, N.V. The influence of deltalycyn and transcranial cerebellar stimulation upon recovery of retina after photo stress in patients with diabetic retinopathy. Rev. Med. Chir. Soc. Med. Nat. Iasi 2014, 118, 1068-1073.

…there are also several more from this lab during this year.

Kutilin, D.S.; Bondarenko, T.I.; Kornienko, I.V.; Mikhaleva, II. Effect of delta sleep-inducing peptide on the expression of antioxidant enzyme genes in the brain and blood of rats during physiological aging. Bull. Exp. Biol. Med. 2014, 157, 616-619.

Riga, D.; Riga, S. Brain lipofuscinolysis and ceroidolysis--to be or not to be. Gerontology 1995, 41 Suppl 2, 271-281.

Riga, S.; Riga, D.; Schneider, F.; Halalau, F. Processing, lysis, and elimination of brain lipopigments in rejuvenation therapies. Ann. N. Y. Acad. Sci. 2006, 1067, 383

Brief intro to DSIP, more to come...

I’ve mentioned it but have yet to really describe it here on this blog: Delta Sleep-Inducing Peptide (DSIP), a neuropeptide first discovered in rabbits. It is a longer peptide than epitalon: Тrр-Аlа-Gly-Gly-Asp-Ala-Ser-Gly-Glu

It is suspected to have a low half-life due to amino peptidases that cleave after the Trp. However, that is really only one amino acid in so it may still serve a purpose in the body after this cleavage. It is claimed to have influences on cortisol levels, prolactin, and the activity of N-acetyl transferase (possibly involved in conversion of serotonin to NAS?).

I had been using DSIP from a certain source previously but I have it from a new source now that has described the sequence as Trp-Ala-Gly-Gly-Asp-Ala-Ser(PO3H2)-Gly-Glu. The serine is phosphorylated. There has been some suggestion that phospho-DSIP is more potent for sleep purposes [Kimura & Inoue, 1989]...and also less potent...[Tsunashima, et al., 1990].

A couple weeks ago I bought a TON of Phospho-DSIP thinking that with a greater potency, I could take less of it. Last night I broke open the first container and took the dosage I would normally take for DSIP (~1mg) by subcutaneous injection (on accident, my injector missed the vein) and intranasally. No improvement of sleep was observed at all. This could be due to the epitalon having potentially lasting effects. I plan on continuing to try Phospho-DSIP for the next few days to account for that.

Unfortunately, I strongly suspect I am going to take a heavy loss on this one. We’ll see - I am still holding out hope that it isn’t true.

More information on DSIP to come as I feel like (mostly: have time) writing about it...

Following up with more epitalon

So, last night, I took more epitalon. This time, 5mg by IV at around 10:30pm. Absolutely no benefit to sleep was found (actually it might have even interrupted my sleep). In the morning, I felt fine (not angry) although still fatigued and in need of sleep. Around 10:30am I recognized some irritability and the initiation of a migraine (aura) and took Cordyceps (cause I had nothing else) and Excedrin (cause I immediately went and purchased it). The aura went away and left me with a headache localized to the front of my head. Apparently this is the target location for migraines. I believe this is the first migraine I have had in which the aura has left me (previous migraines (2) with auras have occurred more than 8 years ago). I’ve been drinking a lot of water, so it isn’t from dehydration. I also have increased light sensitivity and neck stiffness. Migraines and light sensitivity are associated with low serotonin levels. ]

Neck stiffness can be related to “Serotonin syndrome” which apparently can happen if a person takes antidepressants and migraine medication. There are numerous other symptoms for serotonin syndrome so I do not believe I quite have that. However, it is clear that there may have been a delayed effect in which perhaps serotonin either spiked and crashed or perhaps was over-converted leaving me with a depletion.

Here is a little more information on the serotonin to melatonin conversion.

Arylalkylamine N-acetyltransferase (AANAT) is the enzyme that converts Serotonin into NAS (melatonin precursor). It acetylates Serotonin (as you can guess) and then NAS is methylated to turn into melatonin via the action of hydroxyindole-O-methyltransferase (HIOMT).

Serotonin ---AANAT---> N-acetylserotonin (NAS) ---HIOMT---> Melatonin

Other actions of NAS include:

Activation of TrkB receptor (moreso through a NAS derivative “HIOC” [Shen, Gahi, et al., 2012])

The half-lives of melatonin and NAS are described as ~30min in rats while HIOC is about 4hrs. Given that HIOC is a NAS derivative, epitalon could also be increasing this (which has neuroprotective effects via TrkB activation). Half-life of serotonin in the platelets and intestine is on the order of days but it is on the order of minutes in the brain. I wonder what would happen if I consumed epitalon.

Anyway, it has occurred to me that perhaps I already have something in my body that does whatever it is that epitalon does in ‘normal people’. I am notoriously young looking for my age, according to a crazy amount of people. If I take it again, it will be a lower dose or consumed. I am beginning to lean towards not doing it again though…maybe I should stick to DISP and/or taking straight melatonin. Btw, taking straight melatonin never really helped me sleep.

Notably, neither has epitalon.

References:

Shen, J.; Ghai, K.; Sompol, P.; Liu, X.; Cao, X.; Iuvone, P.M.; Ye, K. N-acetyl serotonin derivatives as potent neuroprotectants for retinas. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 3540-3545.

A first experience with epitalon

(I am hoping I will have more informative posts but I wanted to put this one up just so I can keep up with recording my experiences.)

Epitalon is a tetrapeptide (Ala-Glu-Asp-Gly) that is based off of epithalamin that has been extracted from the pineal gland. It has been found to stimulate melatonin synthesis and influence cortisol secretion.

Last night I tried a nasal dosage of 5mg resuspended in 300ul of bacteriostatic water at midnight. Since I have had good experienced with DSIP and there is suggestion that epitalon may benefit sleep I thought, why not? I found that I had improved sleep but not nearly to the level I experience with DSIP (it still took me a while to fall asleep and I still woke in the middle of the night), abnormal nightmares and woke up in a surprisingly bad, irritable mood. Since this is my first experience with epitalon, I definitely can’t make any conclusions and doubt I should trust any subjective determinations as well.

However, the bad mood intrigued me. That was very abnormal for me (as was the nightmares). My first thought was…serotonin. I have had a rocky history with serotonin. I don’t take 5-HT and am an individual diagnosed with “Substance-induced Bipolar” due to a history of tricyclic antidepressants causing this pathology. I decided to look into whether or not epitalon was known to influence serotonin. Due to the limited information on epitalon, I also looked into epithalamin.

In one study, rats were injected with 2.5mg/kg epithalamin in which serotonin, N-acetylserotonin and melatonin was found to peak at night for young rats (apparently only melatonin in older rats) [Bondarenko & Anisimov, 1992]. Unfortunately, I could only read the abstract for this paper. Epithalamin is suspected to increase metabolism of serotonin into melatonin. So, there’s my answer: yes, serotonin is influenced. It will be interesting to see if I experience a rebound effect.

N-acetylserotonin (NAS) turns out to be an immediate precursor to melatonin. Perhaps, actually- a factor in my sleep issues is, in fact, related to my issues with serotonin. NAS has also been implicated in having antidepressant and cognition-enhancing effects [Oxenkrug & Ratner, 2012] with decline of NAS being a factor in age-associated decline.

The following links should be helpful if looking for more information:

http://joshmitteldorf.scienceblog.com/2014/06/26/v-n-anisimov-russian-optomist-on-longevity/

http://steroid.es/epitalon.html

I’m not sure how I feel about this. I know I have “serotonin issues” but I also don’t know what that “means”. All I know is that I don’t know enough that I am comfortable messing with it.

I have observed some negative emotional effect with DSIP as well, just not to the extent that I experienced in this one case with epitalon. It could also be a ‘starter’ effect. It could also be that DSIP and epitalon do the same thing with serotonin. However, I doubt their actions are the same. Subjectively, DSIP has helped me sleep absolutely while generally feeling good in the morning with potentially some irritability later in the day. Knowing the half-life of both of these peptides would be helpful. I think I recall seeing something about “20hrs” for DSIP but I definitely need to check my sources.

Oh yeah, just a note: Mike also took this with me. He woke up pretty happy (he is usually an angry one) with weird dreams but no nightmares.

References:

Bondarenko, L.A.; Anisimov, V.N. [age-related characteristics of the effects of epithalamin on serotonin metabolism in the pineal gland of rats]. Biull. Eksp. Biol. Med. 1992, 113, 194-195.

Oxenkrug, G.; Ratner, R. N-acetylserotonin and aging-associated cognitive impairment and depression. Aging Dis 2012, 3, 330-338.

Purpose.

This blog is based off of a philosophy. I could describe to you my perception of "Justice" but I'll make this short. I believe that all things are deserved. Maybe you've done nothing inappropriate yet you get hit by a car. In such an instance, you deserve to be hit by a car simply due to being in the wrong place in the wrong time. Reality aligned such that you were, in fact, hit by a car. It didn't matter that you didn't know better.

However, if you did know better (perhaps, if you knew something you could not have known), you could have avoided being hit by a car. More information provides you with seemingly more "power" over your fate. There is only so much information that you can obtain, of course, and you are forced to make decisions on your limited knowledge of yourself and the world around you.

If you do deserve everything that occurs, (in that, 'chance' or 'luck' remains 'fair' in that it exists based on physical realities) then what can you do? Doesn't this simply mean that you have no power over your own end points? I do not believe this. I believe there is honor in Endeavor. That is, if you Strive to deserve better, maybe...just maybe...you will deserve better; you will be 'better' and have 'better'. That is the one thing any person can do in this world, Strive.

What goal is more appropriate in one's life than to become better than one's own self [and, in doing so, being a positive factor or influence to the rest of the world]? To strive to deserve better, you must strive to understand more about your own body, mind, and about the world that surrounds you and influences you. The world is full of indefinite information that you can use towards this purpose. Where can you start? Start with what you have the most control over: yourself.

This is my philosophy. It is one reason I became a biologist. To understand other people, you must first understand yourself. To become a better person in any way whatsoever, you must first understand yourself. This may be a goal that is ongoing but the closer you get to understanding you 'algorithm', as I like to call it, the greater your ability is to manipulate it in ways you believe to be beneficial to your own body, your own mind and to the other bodies and minds that interact with yours.

The following is a quote from Wikipedia:

Nootropics (/noʊ.əˈtrɒpɨks/ noh-ə-TROP-iks)—also called smart drugs, memory enhancers, neuro enhancers, cognitive enhancers, and intelligence enhancers—are drugs, supplements, nutraceuticals, and functional foods that improve one or more aspects of mental function.

This is the definition of 'Nootropics'. Becoming a better human, to me, means I start with improving the ability of my brain to collect information, retain information, utilize information, and make beneficial decisions regarding the one thing in this world I know I have some 'control' of: my own brain and body. I wanted to start this blog not only for my own self to have a log of my progressions but so that others can potentially benefit as well. 

I hope you are interested in "Striving" as I am - but if not, perhaps you will at least be entertained and educated. :)