Even if we get full lifestyle benefits, so what? Average
person's longevity gain from the eradication of cancer <=3.2 years
of life. Ischemic heart disease? <=3.55 years. Both together <=
7.83 years. Both, plus all circulatory diseases and diabetes:15.3 years.
(And, hint: we’re already living pretty healthily …).
Retarding aging to extend life span. Logically includes healthspan!
Only one proven intervention: CR [CRON] – and that
in rodents! Hence, warning: maximum
speculation follows!!
What factors are associated across mammalian species, and within
mammalian spp AL [ad lib] vs CR, with slower aging and extended maximum
lifespan?
Only 2 AFAIK [as far as I know]:
- Mitochondrial ROS issues:
mtROS production, mtDNA (not nuDNA) damage, mt membranes oxidative
susceptibility inversely associated with max LS interspecies, and reduced
by CR.[187],[188]
- Antioxidant enzymes inversely associated with max LS! 187
- Dietary AOs, and prob. AO enzymes, do not reduce these factors
and do not affect aging.
- You must reduce production.
- mtROS production is the great majority of ROS in vivo.
- Food e- moved to NAD+ (forming NADH) by glycolysis and then
Krebs/Citric Acid/TCA cycle.
- NADH transfers e- to Complex I, passed along ETS to pump protons,
create electrochemical gradient for Complex V (ATP synthase):
hydro dam system, Complex V (ATP synthase) a literal turbine.
- “Fumbling” by CoQ in transferring e- from Complex I to Complex
III allows e- to react with O2, forming superoxide.
- In CR and longevous spp, lower mtROS production occurs because
of less reduction of Complex I by NADH. Fewer e- pass thru’ CoQ,
fewer ‘fumblings.’ 188
- Interspp difference genetic by definition; perhaps Complex I structure?
- de Grey proposes CR redirects NADH to PMRS.[189]
Explains lower ROS production, Complex I location, no reduction
in metabolic rate.
- Also (unbeknownst to him) lower peak sprint speed in CR (seen
in rodents[190]
and anecdotally in some humans (eg. me!)) despite much higher
overall activity levels (“CR-induced hyperactivity,” longer
running at any age, continuing running after AL are dead); consistent
w/high NADH levels reported by Dr. Robert Lord (MetaMetrix)
in Society subjects?[191]
- Intervention: R(+)-lipoic acid.
- Hagen and Ames: R(+) reduces mtROS production, improves mt
function, lowers mt damage in normal, healthy aging rodents
(no significant effect in youngsters).[192],[193]
- Reducing ROS generation or just mopping up afterward?
Hagen (personal communication) and de Grey think the latter
most likely. However:
- R(+) specifically reduced to DHLA in mt PDH by NADH, leaving
NAD;[194],
[195],[196]
less NADH means fewer e- transfered to Complex I: lower
ROS?
- In cell culture[197]
and in diabetic rodents,[198]
NAD:NADH is indeed increased. (Latter study used racemate;
R(+) should mean higher ratio in mt, lower in cytosol.
- Packer believes that increased NAD:NADH is responsible
for improvements in diabetic neuropathy (corrects for diabetic
hypoxia). 197
- Diabetics overexpress PMRS;[199]
consistent with high NADH:NAD and need for use of PMRS as
exit valve. Consequent cell-surface reductive stress would
explain high oxLDL in NIDDM (mechanism proposed in MiFRA
for how so few cells drive oxidative stress thru’out the
body.[200]).
- Alternatively/additionally, DHLA can quench ubisemiquinone
(CoQ radical which causes fumbling) in membranes in vitro.[201]
- Even racemate LA reported to reduce cochlear mtDNA
‘common deletion” in normally-aging rodents.[202]
- So why no LS bennies from racemate? Not enough
effect, due to low R(+) content and interference of R(+)
reduction by S(-) 194? Negative side-effects of S(-) (eg.
thru’ reduced GSH recycling, NADPH?). Dose? (Seidman used
300 mg/kg; after metabolic scaling (300-400 g rats), human
equivalent 17.659 g! LEF studies used human-equivalent 518
mg.[203]
at standard energy density).
- R(+), not S(-) or racemate, increased “max LS” in athymic
mice (weak evidence: short-lived strain, increase only
based on 2 outliers in small cohort).[204]
- NIA-funded Hagen and Ames LS study with R(+)/ALCAR cocktail.[205]
- Dose: Human-equivalent 612.6 - 1225.2 mg.[206],[207],[208],[209],[210],[211]
Voodoo: coincidental equivalence to RCT dosage for racemate in diabetes,
AD. But Seidman et al 203 and LEF LifeSpan studies 4, 203
(using racemate, NB) might suggest higher dose.
- Intervention 2: Metformin + R(+)
- Roth and Lane: metformin appears “to mimic some of the bioeffects
of [2-deoxyglucose] without apparent toxicity. Preliminary experiments
suggest that [metformin] can increase median and maximal survival
of rats to the same extent as 30% CR.”[212]
Spindler quoted as claiming ~20% increase in LS.[213],[214]
- Most assuming works thru’ antidiabetic mechanisms (increased
insulin sensitivity and glycolysis inhibition), and perhaps
crypto-CR noted by Patrick[215]);
this would likely be irrelevant in normal, healthy folk
(basic weight-loss program (7% weight reduction thru' low-calorie,
low-fat diet and moderate exercise (eg. brisk walking),
for at least 150 min/week) more effective than M in preventing
the conversion of prediabetics to full fleged NIDDM);[216]
“Metformin does not improve insulin sensitivity nor insulin
secretion in obese female patients with normal glucose tolerance.”[217]
But:
- Gene expression changes for wider range of effects
that overlap CR. 213 “These findings suggest that metformin
has more beneficial effects than the reduction of blood
glucose and insulin, and that it may be an authentic
anti-aging therapy.”
- Much closer overlap than other diabetic drugs (incl.
insulin-sensitizing ’glitazones).
- Metformin inhibits
Complex I in vitro[218] and ex vivo.[219]
- Associated in vitro with inhibition of gluconeogenesis
from L-lactate 218 – observed in vivo as dangerous lactic
acidosis side-effect.
- “Because it is established that [metformin] is not
metabolized, these [ex vivo] results suggest the existence
of a new cell-signaling pathway targeted to the respiratory
chain complex I with a persistent effect after cessation
of the signaling process.” 219
- “We conclude that the drug's pharmacological effects
are mediated, at least in part, through a time-dependent,
self limiting inhibition of the respiratory chain that
restrains hepatic gluconeogenesis while increasing glucose
utilization in peripheral tissues.” 218
- De Grey was intrigued, even before Roth’s announcement:
“Interesting … I think that TOTALLY inhibiting the respiratory
chain is unconditionally bad (at least if the affected
cells accumulate), but partial inhibition may be very
different” depending on “how the cells react to the
inhibition” (per his CR model).[220]
- More evidence for R(+)? In isolated perfused rat liver,
“RLA reduces hepatic glucose release by inhibiting lactate-dependent
glucose production in a concentration-dependent fashion.”[221]
- Previously observed in vitro,[222]
and “antigluconeogenic effects of lipoic acid in liver
can be attributed largely, if not entirely, to sequestration
of intramitochondrial coenzyme A” (??).
- ”When transported into the mitochondrion, pyruvate
[product of glycolysis used by TCA to reduce NADH] encounters
two principal metabolizing enzymes: pyruvate carboxylase
(a gluconeogenic enzyme) and pyruvate dehydrogenase
(PDH), the first enzyme of the PDH complex [requires
R(+) –MR]. With a high cell-energy charge [high NADH:NAD?-MR],
coenzyme A (CoA) is highly acylated … and able allosterically
to activate pyruvate carboxylase, directing pyruvate
toward gluconeogenesis. When the energy charge is low
CoA is not acylated, pyruvate carboxylase is inactive,
and pyruvate is preferentially metabolized via the PDH
complex and the enzymes of the TCA cycle to CO2 and
H2O. Reduced NADH and FADH2 generated during the oxidative
reactions can then be used to drive ATP synthesis via
oxidative phosphorylation.”[223]
- Net effect on safety of metformin/R(+) cocktail??
- In vitro, “Parallel decreases (30%) in cellular NADH/NAD+
and in lactate/pyruvate ratios were observed in [R(+)-]alpha-lipoate-treated
cells [former should be reflected in latter as re: glycolytic
pathway].” 197
- “Treatment of guinea pigs (250 g weight) with a-lipoic
acid (0.5 mg) for 10 d substantially increased the level
of lactic acid (30% increase with respect to control
values), and decreased the level of citric acid (60%
decrease compared to control). These data have been
interpreted as lipoic acid stimulating the anaerobic
conversion of pyruvic acid to lactic acid, a reaction
that other authors have indicated to occur in both directions.”[224]
- IDDM rodent study: “Gastrocnemius lactic acid was
increased in diabetic rats … and was normal in LA-treated
diabetic rats”.[225]
- Suicide attempts using 10-40 g racemate have resulted
in lactic acidosis. 224
- Human RCT: “lactate and pyruvate before and after
glucose loading were ~45% lower in lean and obese diabetic
patients after LA treatment.”[226]
- Potential synergism of inhibited Complex I (metformin)
+ reduced NADH:NAD (R(+))?
- Dose: PDR, for diabetics: 500 mg bid, increasing by 500
mg weekly, up to 2g; or 850 mg, increasing by 850 up to 2550.[227]
Combine with R(+), 600 mg.
- Safety: Lactic acidosis serious and unpredictable.
- Steve Harris: “Metformin's an especially scary drug
in this regard, causing liver necrosis in those susceptible
without a lot of warning first, and at doses which are (or
were thought to be) more or less therapeutic. … The LDH on
your liver enzyme panel tells you exactly NOTHING about how well
your liver's lactate processing system is working. Nor really the
AST and ALT – they're simply markers of acute liver cell damage
and leakage.” ALT and AST “won't tell you that you're close to …
lactic acidosis … Don't think of metformin like Jack Daniels or
statins, think of it like digitalis and coumadin. [Cf PDR: “Side
effects cannot be anticipated.”] 227 The idea of skinny nondiabetic
calorie restricted laypeople willy nilly using it as part
of a life extension program in the absence of good data for
the pro side, and probably without good lab support in many
cases, scares me. Not a good idea.”
- Per LEF,[228]
“According to the Physician's Desk Reference, clinically significant
responses in Type II diabetics are not seen at doses below 1500
mg a day”. Not in online version 227 …
- IMO: Not ready for prime time. This is a potentially toxic
xenobiotic drug, and we’re basing all of this on a single, unpublished
rodent study!! Wait for repetition (Spindler, Roth).
- Negative Intervention: Avoid n3 HUFA (EPA/DHA).
- As noted, mt inner membrane (MIM) ‘peroxidizability index’
(number of double bonds/FA in membrane PL) inversely associated
with max LS; aging increases, and CR reduces, MIM index via
lower HUFA, esp n3 HUFA and esp DHA.[229]
Possibly related to membrane peroxidizability and physical
attachment of MIM to mtDNA (ROS damage to MIM à mtDNA deletions).
- Feeding rodents fish oil increases mt inner membrane DHA.
See details at ([230]).
- In parallel, unusually low desaturase activity consistently
observed in human CR. 191
- Cardio benefits seen equally or more so with increased ALA
intake, per epidemiology and RCTs. 230,[231],[232]
- No benefit to more than 1-2 fish servings/week in any case,[233],[234] so no justification for supplementation.
- Dose: Maximum avoidance. Ensure adequate intake of n3 with
2-8 g ALA.
- Rate of AGE Accumulation:
Inversely correlated across species; not fully correlated with
blood sugar levels (eg “hyperglycemic” hummingbirds,[235] but also seen within mammalian class[236])
and hence evidently genetically regulated. Miller et al zeroing in on
such genes in mice.[237]
CR lowers both blood sugar and AGE, and “markers of skin collagen
glycation and glycoxidation rates can predict early deaths in AL and
CR C57BL/6NNia mice.”
- Nearly all “anti-glycation” nutrients have only ever been tested
in vitro, and work at Schiff base formation, not AGE formation
per se: ineffective strategy in vivo (sheer stoichiometry and reversibility).[238]
In vitro conditions extremely misleading in any case. 238
- Includes carnosine
- No in vivo data.
- In vitro, prevents Schiff base formation, but little
effect on AGE.[239]
- Recent LEF ad: “research has shown that metals, predominantly
copper, are culprits that promote
excess glycation … A new study[240]
concludes that carnosine not only inhibits glycation
earlier than aminoguanidine, but that it is 625
times more potent at chelating ... the harmful
copper. This new study confirms that carnosine is the most
effective anti-glycating agent.” Misleading – see
cited study:
- Looking for mechanisms and to undo confounding,
not clinical utility.
- In vitro, and not even measuring AGE formation!!
- Physiological concentration already 5 times IC50 for chelation
mechanism!
- Chelation of unlikely mechanistic significance in vivo.
238
- “Earlier” not “better” re: AGE.
- OTOH, in vitro studies suggest alternative mechanism for in
vivo effect via increased proteolysis;[241],[242]
but physiological relevance still unknown.
- Aminoguanidine does not inhibit AGE formation
in areas distal from the circulation (skin and tail collagen),[243]
is quite toxic (antinuclear antibodies (sign of autoimmunity) and
flulike symptoms) and of no clear benefit in diabetic humans at
300-600 mg/day,[244] and was of no benefit in the LEF LifeSpan studies.
4
- Intervention 1: Pyridoxamine
- Post-Amadori AGE inhibitor. 238,[245]
- Extensive animal evidence: lowers AGE (&ALE) accumulation,
including in skin and tail collagen;[246],[247],[248],[249] prevents or treats nephropathy in insulin-resistant
hyperlipidemia, 246 NIDDM[250] and IDDM, 249 with stronger effects than aminoguanidine;[251]
reduces atherosclerosis in hyperlipidemia; 246 reduces retinopathy
in IDDM. 247
- Human Phase II Studies: Well-tolerated at doses which
create plasma levels similar to those in rodent studies;[252]
in 12 patients with diabetic nephropathy, “The average decrease
from baseline in 24 hour urinary albumin excretion was 32% at
day 45 ... Three patients receiving Pyridorin had also converted
from macroalbuminuria [>300 mg albumin excretion/24h] to
microalbuminuria [<300 mg/24h] by the end of the treatment
period.”[253]
- “Should” primarily work on extracellular proteins (connective
tissue, some parts of glomeruli, retina), as phosphorylated
upon (regulated) intracellular uptake.
- Dose: 500 mg PM dihydrochloride (~300 mg
“elemental” PM) used in Phase II study, yields similar plasma
levels to 2 g/L used in rodent studies.
- Possible neuropathic side-effects: observed
with pyridoxine: cutoff dose controversial. LOAEL 500
mg pyridoxine; NOAEL 200 mg. No increase in pyridoxine
seen with PM, 253, but in vitro, pyridoxine and pyridoxamine
of equal neurotoxicity.[254]
- Unusual B6 metabolism in CR rodents[255]
and possibly humans. 191
- Intervention 2: Benfotiamine
- Lipophilic thiamin derivative: higher bioavailability and
cellular uptake (thiamin absorption at both levels very
limited: GI can’t absorb more than ~8-12 mg thiamin at
a time, 155, 156, 157, 158, 160 vs. dose-proportional passive
diffusion of Benfotiamin). [256],[257],[258],[259],[260]
- Benfotiamin much more potently elevates thiamin pyrophosphate
(thiamin coenzyme) and activates transketolase (key thiamin-dependent
enzyme). 256, 257, 258, 259, 260
- Mechanisms: TPP itself a post-Amadori AGE inhibitor (weaker
than PM); 245 key mechanism pentose phosphate shunt:
- Neurons, glomeruli, retinal capillaries’ glucose uptake
is not insulin-dependent, but follows blood levels.
Hence, high blood sugar (postprandial state, insulin resistance,
(N)IDDM) causes intracellular hyperglycemia.
- Hyperglycemia overloads glycolytic pathway, and leads to
increased mtROS, which deactivates key glycolytic enzymes.
- Causes buildup of triosephosphate intermediates (reactive
dicarbonyls): causes intracellular AGE.
- High levels of transketolase activity allow for “shunting”
into pentose phosphate pathway.260,
[261],[262]
- Benfotiamine proven to reduce AGE burden in diabetic
humans[263]
and animals. 260,
[264]
- Benfotiamine proven to prevent and treat diabetic complications
(neuropathy in RCTs, [265],[266],[267],[268], [269],[270],[271],[272]
retinopathy260 and nephropathy[273] in animal studies). Megadose thiamin less effective
in animal studies, 264, 273 ineffective in preliminary data
from ( 264)
[274] and in head-to-head human trial. 269
- Much less likely important in normals or CR folk, in whom hyperglycemia
rare (exception (?): postprandial period).
- Dose: 320-400 mg first month, 120-160 mg thereafter
in diabetic neuropathy.
- Intervention 3: Interprandial arginine
- Carbonyl scavenger. 238 Reduces AGE accumulation in diabetic rodent
kidneys[275],[276],[277] and hearts;[278]
results in humans inconsistent.[279],[280]
- Dose: 2g/day, taken ~40 min before meals to address
postprandial dicarbonyl surge.[281]
- Alternate (even more
speculative!) CR-Mimetic Make-the-Case Speculations:
- SIR2, PNC1 Gene Silencing [282] ,[283]
- Free NAD+ or NAD:NADH ratio prevents inhibition of SIR2.
- Yeast. Mammals do not form rDNA circles; “aging” in yeast entirely
replicative (relevance to mammals questionable: postreplicative
brain, heart, muscle tissues).[284]
If Guarente correct on mechanism (CR in yeast causes reduced
glycolytic flux, hence higher NAD:NADH), possibly irrelevant
(mammals apparently show no reduced metabolism in response
to CR). If Anderson correct (PNC1 converts nicotinamide to nicotinic
acid), greater potential relevance.
- Intervention: R(+)-lipoic acid.
- See above: lowers cytosolic and mt NADH:NAD.
- Insulin/IGF1 Signaling
[285]
- ”Reduced signaling of insulin-like peptides increases the [max] life-span
of nematodes, flies, and rodents.” 285
- CR lowers insulin and IGF-1
- Anti-mitotic (anti-cancer; preserves immune reserve and prevents autoimmunity
(CR)?)
- Reduced mtROS seen in Ames dwarf mice.[286]
- Reduced IGF-1 signalling in mammals does not fully reproduce CR effects.[287],[288],[289]
- Intervention: Benfotiamin?
- Monnier: Activation of PPP by B might reduce glycolytic flux, reduce
deleterious insulin-related signaling.[290]
- I don’t buy it.
- Benfotiamin effective during intracellular hyperglycemia in cells
whose uptake of glucose (via GLUT1) is not insulin-mediated.
- Likely little reduction in glycolysis per se, esp in normoglycemic folk.
- Irrelevant to heart, skeletal muscle.
- Negative intervention: Avoid GH-boosting supplements,
hGH injections, etc.
- PMRS Modulation
- See mt discussion above. De Grey’s e- shunt through PMRS 189 would create
mild REDOX stress. Lawen et al[291] suggest ‘rescue’ of bioenergetically deficient cells
by taking e- at PMRS; could make PMRS e- less toxic, extend
CR LS bennies per MiFRA.
- Intervention: CoQ10?
- Tissue uptake negligible outside of liver and spleen,[292]
so cardio effects not due to mt enrichment. Lawen et al 291
show that CoQ unloads e- from PMRS; proposed as mechanism.[293]
- Several LS Studies Negative:
- Favorable, but not definitive, result from Bliznakov:[294]
injects 50 mcg/week/mouse, beginning at ~510 days (~51 human
years); av’g LS increased to ~728 from ~650 days (12% increase);
max LS either unrecorded or 1084 days. Promising, but no clear
effect vs. optimally-cared-for rodents; pharmacokinetic issues.
- Null effect from 10 mg/kg/day oral CoQ in rats (scales to 213 mg[295]).[296]
Older (16 mo) dams of experimental populations supplemented
during pregnancy; complications? (Not teratogenic; did
not affect litter size; no difference in BW thru’out lifespan).
- Another null effect from Lonnrot et al mice:[297]
prob. Scales to ~100 mg/day.
- Null effect, or even slightly unfavorable, LEF LifeSpan studies,
alone or in combination; 4 dose 86 mg.
- Steve Harris[298] unpublished LS study at human-equivalent 500-750 mg/day:
robust 23% curve-squaring. Video suggests v. healthy.
- Extended LS from CoQ-free diet in Clk-KO flatworms[299]
irrelevant to mammals: mutant strain probably CoQ-deficient,
so CoQ-free diet causes halt in respiratory chain.[300]
- Most studies[301] (but not all[302])
report lower tissue CoQ with CR; not relevant to present mechanism
or pharmacokinetics of CoQ itself, and could be a limiting factor
rather than a mechanism.
- Dose: 750 mg/day, per Harris study; 100 insufficient,
per Lonnrot, and >200 mg normally required to achieve therapeutic
levels in human heart failure (>2.0 mcg/L), w/ highly variable
bioavailability.[303]
,[304]
1200 mg needed for clear-cut effect in Parkinson’s;[305]
responders in prostate cancer case series all achieved >
3.0 mcg/L, nonresponders all < 2.0 mcg/L, at 600 mg/day.[306]
Use softgels or dissolve in oil; take with fat-containing
meal.
- Carnosine?
- Reverses cellular senescence in vitro.[307]
,[308]
- In vitro!!
- -Role of cellular senescence in aging debatable; possible indirect
effects thru’ secreted factors.[309]
- Selective inhibition of cancer cell growth: no effect on normal[310]
or embryonic stem cells.[311]
- In vitro!!
- In SAM-P mice, increases mean LS by 20%, reduces some ‘aging’ phenotypes
(hair fullness and color, skin ulcers, periopthalmic lesions,
spinal curvature) and normalizes binding of NMDA receptors,
MAOb, Na/K-ATPase.[312]
- SAM-P mice are fuckups; still much shorter LS than normal mice.
- No effect on max LS.
- SAM-P mice have ‘naturally’ low carnosine levels.[313]
- Painfully speculative: zero data on normal, healthy organisms,
no epidemiology, nada. But intriguing …
- Dose: Good question!
- 100 mg/kg used in SAM-P 312 and in studies on ischemic assaults.[314],[315],[316]
Human-equivalent ~1000 mg.
- In rodent studies, human-equivalent 500 mg/day does not elevate brain
or muscle levels
[317],[318],[319]
and do not protect rodent vascular
system from fructose-rich diets.[320]
Human-equivalent doses of ~945 mg a day raise tissue levels
317, 320 and protect vascular system.[321]
- However, carnosinase enzyme degrades carnosine to beta-alanine
+ histidine. Rodents only have a nonspecific dipeptidase
with carnosinase activity by default. Humans have an additional,
specific serum carnosinase;[322]
,[323]
higher than proportional scaled doses will be required.
- Strangely, oral supplementation leads to increased urinary C, yet no
increase in plasma levels, in humans;[324],[325]
“it seems that absorbed carnosine may be very rapidly cleared
from the plasma and sequestered in some compartment before
it is excreted by the kidneys.” 324 Alternately, hydrolyzed
and resynthesized?
- IAS claims lower doses reduce urinary MDA;[326]
MDA is a bad marker of oxidative stress, and in any case
also seen in rodent studies using TBARS, despite a failure
to increase tissue levels (associated with conserved vitamin
E in liver). 318 Uncontrolled, unpublished trial by unpublished
‘researcher.’
- Dose Conclusion: Substantially > 1 g will be required;
1500 mg?
- High-protein diet leads to higher C absorption;[327]
Met-free diets reduce absorption.[328]
Prob due to density or activity of dipeptide transporters.
- Various dipeptides (eg glycyl-L-proline, alanine) compete with C for
transporters, inhibit absorption:[329]
take on an empty stomach.
- ALCAR issues. Human RCTs for Alzheimer’s disease;[330]
also seems effective for spatial learning in healthy young subjects.[331]
- Improves various aspects of mt structure and function in rodents;[332],[333],[334]
supplementation in middle-aged (16 mo) rats had mixed effects
on pathology but improves survival to 22 mo (38/45 vs. 29/45
survivors).[335] But Hagen and Ames reported increased mtROS production
in old supplemented rodents.[336]
Yikes!
- Only observed in old rodents. 336
- Observed at v. high dose: 1.5% in drinking water, scales to 12.9
g.[337]
In dose-ranging studies, “lower concentrations of ALCAR
(0.15% and especially 0.5% [scales to 1.29 to 4.3 g]) ameliorated
the age-associated decline in ambulatory activity (TABLE 2)
and mitochondrial cristae loss in the dentate gyrus of the hippocampus
(FIG. 12) more effectively [MR's emphasis] than the 1.5%
dose. The lower doses had no effect on protein oxidation, in
contrast to the 1.5% dose, which caused an increase in protein
carbonyls in the brain. Furthermore, lower doses (0.15%) also
reduced the age-dependent increase in malondialdehyde … more
effectively than the 1.5% dose”. 332 Likewise, “Lower doses
of ALCAR, that is, below 1.0% (wt/vol) in the drinking water
did not increase hepatocellular oxidative stress”. 333
- Tissue-specific effects: In heart, even high dose (1.5%
in drinking water, = 12.9 g) caused “no alterations in oxidant
production in isolated cardiac myocytes ... Furthermore, myocardial
levels of ascorbic acid, which decline significantly (P <
0.02) with age (FIG. 5) did not exhibit a further ALCAR-induced
decline”. 333 (Cf. tissue-specific effects of aging and CR on
mt function[338],[339]).
- ALCAR reduces mtDNA deletions in cochlea per Seidman at
massive dose (17.7 g, scaled); 202 again, tissue-specific (local
bioavailability eg)?
- mt structural improvements (retarded loss of cristae) 332 at
lower doses argue for direct benefit, in addition to metal chelation,
improved bioenergetics, and other antioxidant mechanisms.
- R(+) corrects ALCAR-induced mtROS even at high dose; 334, 336 as argued
above, likely a real, primary effect
- Dose: 1.29 to 4.3 g – again, suggestive coincidence, as this
is the standard therapeutic range for AD. 330 Conservatives
might lean lower than lower end, but not clinically supported.
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