Loss of Lipid Chaperones Mimics Some Aspects of Calorie Restriction
The research I'll note today involves genetic knockout of fatty acid-binding proteins in mice, something that appears to slow the development of metabolic disorders associated with excess fat tissue and aging - there is a lot more funding for investigation of the former cause as opposed to the latter cause, sadly. The work is, I think, chiefly interesting for mimicking some of the cellular effects of calorie restriction, while preventing some degree of the metabolic decline that accompanies aging, but achieving all of this without either extending life or improving the other usual functional measures of aging: loss of strength, cognitive decline, and so forth. In principle that sort of result should be quite hard to achieve, and indeed I can think of few lines of research in which this happens with any reliability in short-lived species such as mice. They are sensitive to environmental and genetic interventions, with very plastic life spans in comparison to those of longer-lived species such as our own. Anything that constitutes a significant improvement to health should also extend life.
Extending the duration of measures of health without extending life span is hard precisely because aging is determined by cell and tissue damage, a consequence of that damage, just like the decline of any complex machinery. There are only a few options when it comes to how to proceed: fix the root cause damage, try to compensate for loss of function by adding more capacity, or try to prevent secondary effects that result from the primary damage. Medicine to date has focused on the latter two options, which is precisely why it produces only marginal, incremental benefits. Making a damaged machine work well without repairing the damage is exactly as challenging as it sounds.
The genetic intervention carried out by the researchers in this paper has the look of a method of preventing secondary effects, some of those resulting from weight gain and fat tissue dysfunction in aging, by interfering in the processing of fats. That is no doubt an overly simplistic consideration. For example, we know that simple surgical removal of visceral fat significantly extends life span in mice, and yet the genetic approach here, that reduces weight gain, has no such outcome. A first thought is that it is possible that removal of fatty acid-binding proteins is causing harm in other areas of biochemistry, and thus shortening life even as it helps on the metabolic front. So while the researchers discuss their data as evidence of a decoupling of metabolic health and life span, and make a fair case, it may or may not be what is happening under the hood.
Targeting 'lipid chaperones' may hold promise for lifelong preservation of metabolic health
Scientists found that mice that lack fatty acid-binding proteins (FABPs) exhibit substantial protection against obesity, inflammation, insulin resistance, type 2 diabetes, and fatty liver disease as they age compared with mice that have FABPs. However, this remarkable extension of metabolic health was not found to lengthen lifespan. FABPs are escort proteins or "lipid chaperones" that latch onto fat molecules, transport them within cells, and dictate their biological effects. Previous work found that when FABP-deficient mice were fed high-fat or high-cholesterol-containing diets, they did not develop type 2 diabetes, fatty liver, or heart disease.
Metabolic health typically deteriorates with age, and researchers believe that this contributes to age-associated chronic diseases and mortality. Studies have shown that high-calorie diets impair metabolism and accelerate aging; conversely, calorie restriction has been shown to prevent age-related metabolic diseases and extend lifespan. In the new study, researchers examined metabolic function in multiple cohorts of FABP-deficient mice throughout their life. They found that FABP deficiency markedly reduced age-related weight gain, inflammation, deterioration of glucose tolerance, insulin sensitivity, and other metabolic malfunctions. This effect was more strongly observed in female than male mice. Surprisingly however, they did not find any improvement to lifespan or preservation of muscular, cognitive, or cardiac functions with age.
The researchers saw striking similarities between the alterations in tissue gene expression and metabolite signatures in the genetic model of FABP-deficiency developed for this study and the alterations that occur due to calorie restriction. The findings suggest that it may be possible to mimic part of the metabolic benefits of calorie restriction by targeting FABPs. In addition, by examining the molecular differences between these models, it may also be possible to identify other pathways that contribute to longer life span or alternative strategies to prevent metabolic diseases.
In this study, we have shown that the lipid chaperones FABP4/FABP5 are critical intermediate factors in the deterioration of metabolic systems during aging. Consistent with their roles in chronic inflammation and insulin resistance in young prediabetic mice, we found that FABPs promote the deterioration of glucose homeostasis; metabolic tissue pathologies, particularly in white and brown adipose tissue and liver; and local and systemic inflammation associated with aging. A systematic approach, including lipidomics and pathway-focused transcript analysis, revealed that calorie restriction (CR) and Fabp4/5 deficiency result in similar changes to the adipose tissue metabolic state, specifically enhanced expression of genes driving de novo lipogenesis and non-esterified fatty acids accumulation. Furthermore, CR was associated with reduced FABP4 in circulation, providing a potential molecular mechanism underlying its metabolic benefit.
The extension of metabolic health by Fabp deficiency is long-lasting even in aged female mice. However, despite the remarkable protection in glycemic control, insulin sensitivity, inflammation, and tissue steatosis in Fabp-deficient mice, we did not observe any change in the lifespan curves. We also did not detect preservation of cardiac, muscular, and cognitive functions. In females, there was even a mild decline in cardiomuscular function associated with Fabp deficiency during aging. These observations support the concept that, in higher organisms, significant improvements in metabolic tissue inflammation, metabolic tissue integrity, and systemic metabolic homeostasis may not necessarily lead to increased longevity.
Our studies with Fabp-deficient mice now provide genetic evidence in animal models that prolonged metabolic health, particularly glucose and lipid homeostasis, may be uncoupled from lifespan and maintenance of cardiac, muscular, and cognitive systems, which partially recapitulates the human pathophysiology observed during intensive glycemic control. Furthermore, it is intriguing that there is a considerable overlap between the unique lipidomic profile, especially in adipose tissue, of Fabp-deficient animals with those that have been subject to CR. Future studies exploring the similarities and distinctions between these models in multiple sites may provide additional insights into specific pathways and their regulation of healthspan and lifespan. Further exploration of the disconnect between metabolic health and longevity may also shed light on alternative therapeutic approaches against diabetes and possibly other metabolic diseases that are associated with aging as a risk factor.
" These observations support the concept that, in higher organisms, significant improvements in metabolic tissue inflammation, metabolic tissue integrity, and systemic metabolic homeostasis may not necessarily lead to increased longevity. "
Doesn't seem to lead to significantly better health either according to their own opinion:
"they did not find any improvement to lifespan or preservation of muscular, cognitive, or cardiac functions with age."
Hey there,
''genetic evidence in animal models that prolonged metabolic health, particularly glucose and lipid homeostasis, may be uncoupled from lifespan and maintenance of cardiac, muscular, and cognitive systems, which partially recapitulates the human pathophysiology observed during intensive glycemic control''
It is very confusing, but I am sticking to the 2 things : health and longevity; two different things, yet 'the same' (if we can even say it that way). Interconnected and interDependent; while inter -INdependent Too. We thought it was easy to understand health = longevity, longevity = health. 'Solved'. It's more subtle and vastly more complex/nuanced in its subtlety (much more shades of grey).
Albeit, the damage part is very true and we can all agree that damages are the major cause of intrinsic aging. With that, we have the rest, like programmed aging (epigenetics/DNA methylation loss) and nuclear chromosome shortening (telomeric termini DNA loss/getting short).
And, of course, replicative senescence (different than oncogene-induced (telomere too low for continued replication/cycling - end of the road Hayflick limit) or spontaneous DDR senescence (which is activated by telomere DDR signal)).
These studies, such as this one here, must research most extreme examples rather than stick with mice (short-lived). You should always compare the longest living creatures (those living decades or even centuries vs a 2 year old mice) for maximal answers. Comparative biology is oftenly more telling because it applies better to us (since we live 30+times longer than mice).
I understand that scientists can't 'wait' after long-lived animals to die/make studies with them and use mice 'quick-model'; but, many studies have come out and given us wealthy of infos from much longer lived animals -that are much closer to us in terms of biology 'needed' to live decades as we do, and, they, do like us. Albeit, it's not all bad just that many of the mice's evolutionnary traits/goals are totally different than ours; as such, many of the things happening in it don't apply to humans. Naked mole rats are already much more appropriate, still not the best though (yet there is a large similarity in the protection that the NMRs have and humans have in common (and that mice Don't have, and hence why they die in 2 years)). Long-lived apes like chimpanzees/gorilla are the best of course.
Health and Longevity can be uncoupled, while still being coupled; like a selective thing whenever it suits (analogous to a couple who are an 'open couple' - it's understood that they can go find someone else for a while (both partners 'accept that' like in a polygamous relationship) - and that couple comes back together the next day as if that 'straying' never happened and 'no harm/no cheating done/polyamorous/gamous all the way' (all understood and accepted)))). I have now realized that the body is a continuous 'balancing 'out/in' thing that will adjust itself depending on the situation it is in; hence, it would engage/disengage into Health or Longevity - depending. Because it continuously balances itself to find that sweet spot that 'works' in the context/biological circumstances that it is faced with as of this moment. It makes think of certain bisexual animals (I meang bigender), they have hermaphrodite quality - if they need to 'become female' right now..they do...they turn female gender...to increase sexual reproduction. Or if they found a 'good female'..they turn male to mate with her....selective selfgenderizing for improved specie reproduction/survival. Same thing, with longevity and health (And reproduction), energy and starvation/famine/calories (CR/mTOR/IGF))).
A study like this one tells me that indeed, healthspan Can be uncoupled from Longevity (Average Lifespan, and Maximal Specie Lifespan). It is not because you are healthy that you live a 1000 years. The aging program continues and damage accumulation too; same for telomere loss, same mitochondrial failure/ATP loss...
I recently read how the Redox is capable of controlling mitochondrial fate, mTOR is responsible for geronconversion to senescence - but many of the hallmarks for that conversion are the damage type : beta-galactosidase, TNF increase, and especially,
mitochondrial ROS emission becoming insufficiently scavenged (ROS producion vs Quenching),
You need ROS because ROS are signaletic/signals...yet if they overbalance (tip balance) towards 'more ROS' then it becomes dangerous - only a 'small' increase of ROS is good - it is an hormetic signal (Hormesis is activated in CR, and this hormesis activates the Redox elements via NRF2/ARE/HSPs..and then autophagy procees to engulf the failing mitochondrias while at teh same time new mitos are created/mito synthesis (mtDNA number is said to equal to lifespan although that is not sure; but in mtDNA mutation disease there is almost always mtDNA deletions, lesions, or reduction of mtDNA copy number; this manifests as 'LOW OXPHOS' the mitos produces less ATP because the ETC/Complex I-V are 'sluggish' from higher ROS or damaged mtDNA (damaged mtDNA makes for faulty signals/faulty mitos that become weak as ATP producers becayse the whole mtOXPHOS ATP is messed up)).
One study showed that mitochondrias have the capacity to revert aging, and I mean in the sense that, if you keep mitochondrias working/high enough ATP there is a possibility that replicative senescence can be twarthed - not necessarily by telomerase (which is absent in post-mitotic somatic cells), but by other means; possibly other members of telomeres (Shelterin complex, KU-67, POT, polymerase, toposoimerase, and others), or possibly by telomerase but in very rare occasional 'boosts' (like seen in babies whom have higher zinc finger domain activation - they activate telomerase very rapidly and then it goes back to sleep - that happens in somatic cells; telomerase could be activated sporadically and this would not increase cancer odds that much - hence 'sporadic' activation (Excess telomerase increase chromosone instability and SCE (sister chromatid exchanges/fusions/recombination errors)))).
IF ATP is kept then we could have the possibility of reversing aging for they would not be cell energy failure; this would allow (now defective) enzymes to come back and do their job (humans lose 50% of ATP power between 0 to 90 years old in their cells). When ATP is too low = apoptosis or senescence depending (since these cost ATP). Cells accumulate junk (lipofuscin) which hinders ATP production (mitos become sluggish)) - thus, the way I see it is we have to control the mitochondrias and it will have immense impact. Diabetes, and other diseases all show reduction in ATP and dysfunctionning OXPHOS respiration in mitos. Intrinsic Aging is characterized by a reductoin of ATP production. Supercentenarians evade that by their cell mitos' mitofusion (their bad midos become fused in a big mass that produces 'Enough ATP' to make it work despit each one being damaged)); plus they show conserved autophagy. It is erroneous to say 'elevated autophagy'...it is correct to say 'preserved/conserved' autophagy because animals with much shorted lives can have Ultra-activation of autophagosome -yet they die very quickly - because their biology could not prevent the damage accumulation - which clogged the proteasome/autophagosome/lysosome... thus, they only saving grace (to not die Even Quicker) is 'hyper activation' of autophagy int hese short-lived animals. In the inverse, animals who live very long lives Don't activate the proteasome - ONLY when it Direly needed because 'some junk is coming in/from 'some damage/injury'''. And, of course, when they do activate it - theirs work much better and faster. Obviously, it was not 'Clogg to Death' like the ones from a short-lived animal. I.E. : to have a functionning proteasome, you need to keep it 'Tidy/empty' and not let it 'degenerate/clogg' because you make it accumulate far More crap then it is capable of 'taking in/degrading' (garbage collection is too loaded and gonna explode soon (the lysosomal mass will keep on rising until degradation is completely impossible; it is a vicious circle of 'more crap in, more difficulty ridding of it' ))).
The mitochondrial potential is the main decider of what happens, ROS determine if the mitochondrial membrane potential is kept or collapses - which activates mPTP (mitochondrial permeability transition pore opening, oftenly with a rise of Ca2+ (Calcium overload because calcium ions determines mitochondrial fate))))). The Redox is capable of quenching mitochondrial ROS emission to a safe level - with aging this changes deeply as the sulphur/cysteine thios and thiol proteins become oxidized - thus not capable of quenching mitochondrial ROS at Complex I-III. One study showed that NMRs (naked mole rats) live 35 years and keep their redox, while a mouse does not; its fibroblast replicate for barely 5 PDs - demonstrating that it has mitochondrial Redox failure very quickly. The study demonstrated taht NMRs thiol cystein residue and thiols proteins/enzymes (such as glutathione reductase, gamma cysteine-ligase, glutathione transferase, thioredoxin, peroxiredoxin, glutaredoxine, glutathione peroxidase,..) stay intact for over 25 years - Just like humans. while mice's become drastically and, especially, Irreversibly, oxidized in less than 2 years. This means Mice Are Not protected like humans and nmrs are. Irreversible Protein-Thiol oxidation is something that is seen in the shortest living animals; what is bad is protein/amino/cysteine-residues damage for it regulates Many things (as they oftenly activate catalytic activity) pertaining to Longevity (which requires Maintenance of Redox homeostasis) rather than just 'health'. DNA residues such as ARG (Arginine), ASP (aspartate), LYS (lysine), ALA (Alanine), LEU (leusine), and of course the DNA telomeric ones T *thymine), A (adenine) G (guanosine), C (cytosine) etc...their function/conservation are crucial for instrinc aging longevity.
One study showed that humans because mV positive by 0.5+mV each year which means the cell Redox milieu becomes oxidized with age, especially in the Cytosol/Cytoplasm - yet, animals who beat humans in longevity don't show that, they maintain an homeostatic frozen redox and thiol proteins that are the same the were 'before' (which means unoxidized, not permanently and Irreversibly oxidized residues as shown in short-lived mice).
Just 2 cent.
Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians
1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032796/
PS: here is another study that demonstrates my point. It shows that the Longest living C.Elegans ever (living 10-Fold longer than regular wild-types (200+ days vs 20 days), in fact there is not a single experiment that has had such an extreme lifespan extension mutation yet. These C.Elegans mutant beat Drosophilas flies in longevity my a mile, going on to live nearly a full year rather than half-a month in their wild-type state. C. Elegans have been used for CR/DAF-2/DAF016 and IGF methods, they were very weak and only increased lifespan by like 20%..this is an extension by a 1000%)). These long-lived mutants (age-1 mg44 F2) have a mitochondrial IMM lipidome reorganisation towards a low PI (peroxidizability index)) by switching from DHA/EPA towards low polyunsaturation in their membrane phospholipids (they basically alter the desaturase/elongase mechanism which alter lipid saturation/unsaturation/polyunsaturation/monounsaturation)). Mitochondrias and, especially, mtDNA were the reason they lived 10-Times longer; they kept intact mitos = kept ATP levels, they kept low peroxidation of membranes thus no peroxidation of the very-close-by mTDNA inside the mitos (for mitochondrial mebranes acts as 'enhancers' of perodixation chains (by their phospholipid Fatty Acids such DHA/EPA which are highly unsaturated polyunsature fatty acids inside their phospholipids in the IMM/OMM (inner/outer mitochondrial membrane, membrane bilayer)). Highly polyunsaturated fatty acids contain longer chains that are susceptible to catalizing lipoperoxidation chains that 'reach' the mtDNA and damage it. In fact, this is seen in humans : humans lose their DHA/EPA/ARA fatty acids when in diseases, they become peroxidized and catalyse the destruction of the near-by mtDNA as they are peroxidized. mtDNA is composed of these residues, ALA,T, A, G, LEU, CYS, C, ASP, VAL, etc....they become oxidized. Since this C.Elegans lives 10 times longer, it is a pure proof that its mtDNA is the 'heart' of where the damage is happening/and causal for it to live 10 time longer. The fact that there is no change to its mtDNA but there is a change to its lipidome is clear indication that the mtDNA is 'spared' by this intervention and allows for an extreme longevity enhancment (like no other so far in any scientic research done till today; this is exception to the rule). Humans have benefitted from the same, they lipid/fatty acid reordering (in the PE/PC, phosphatidylethanolamine and phoshatidylcholine), this allowed humans to have long lives - because their mtDNA was spared just like in this mutant C.Elegans. This means humans and these mutant elegans, protect the DNA (mtDNA especially) residues and this allows for extremely longer lives. But what protects that ? Here, we have a lipidome reordering protection but outside of that, it's the Redox that protects that. This reordering was just a 'ruse' by evolution to ouwit the 'damage' : 'avoid damage' (stop oxidation/oxidative stress) altogether is far more powerful than take damage and try repair it.
''For this study, fatty-acid profiles were compared across a panel of C. elegans mutants that span a *tenfold range* of longevities in a uniform genetic background. Two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway).''
''An inverse correlation between peroxidation index and lifespans of mammalian species has been noted previously [56]. Examples in which extreme longevity is accompanied by membranes of exceptionally low peroxidizability include the naked mole rat [34], the monotreme mammal echidna [57], and, as already mentioned, humans [54]. A similar correlation was also reported within an invertebrate species: the long-lived honeybee queen has PUFA levels well below those of short-lived workers [Queen honey bees live 3 Years, worker honeybees last a few months - ants live years and a Queen Ant lives up to 35 years (!)..same thing happens in it as in the the C.Elegans, mitochondrial lipid reordering towards Unperoxidatively-susceptible milieu (i.e avoid peroxidation/oxidation altogether, thus 'spare mtDNA residues')]''
Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082008/
The problem is what they semantically smash into the "health" definition is just the lack of metabolic diseases.
How often do higher animals and humans die directly from those? Not very often, they would have to develop kidney failure or some other complication.
What metabolic diseases do is increase CVD risk but in this case cardiovascular function was unchanged so obviously no increase in life expectancy should be expected there.
And what about overall fitness? There are a lot of successful people in sports suffering from diabetes, at this point we're pretty good at managing metabolic disorders.
Even the mouse got jack when the benefits to cardiovascular health was removed.
So maybe it's time to admit mice are not worms and humans are neither worms nor mice. Obviously the problems we have wouldn't be with mechanisms operating in the short term, otherwise we wouldn't reach lifespans 40+ times longer than the typical mouse and many hundreds of times more than a worm.
Hi Anonymoose, just a 2 cent,
When I compared a mice and a naked mole rat (NMR) - I realize they are both rodents genus and very similar in size/body/morphology,
but they are different by over 10-fold in lifespan longevity (2-3 years mice, 30-35 years
naked mole rats - and the 'cousin' regular rats, 'ratus norvegicus', ones who live about 3-4 years).
It is true that mice - and NMRs - and regular rats, gerbils and other rodents are not like humans; yet, one of them lives Very closely
to a 'young' human lifespan (35 years); which is quite extraordinary when its cousins don't. It means there is more to the story then meets
the eye and that, certain, rodents (as NMRs or even other mole rats such Damara mole rat but don't live as long), defy the 'trend' as outliers (just like humans are, outliers/exception to the rule in the 'ape' kingdom)
and approach to 1/3rd of human lifespan. That is where I realize that we have more in commmon than we thought - or let's, biology is far more similar than we think - goals differ but biology not that much actually (i.e. you can still mTOR/IGF/DNA and the whole thing is nearly every creature and living eukaryotic cell/there is (some) semblance and (some) semblance in the mechanisms; they don't work all the same way and for same purposes but share homology/blocks).
Same thing for a Queen Ant, that can live nearly 30 years; this is extraordinary, how could such an animal have anything in common with humans
besides a couple cells - it seems, these cells are that common ground and allow such an insect to live long like a NMR or 1/3rd human lifespan. Queen ants and Queen bees feed on royal jelly type of nourishment from the 'low-class' workers who feed them that - this activates zinc-finger motif/stem-cell like vitellogenin genes and even, telomerase, in these insects; then we see lipid reordering in them (like in humans). The effect is that these Queens lives on for years; replicative senescence is twarthed in them just like humans again).
That commonality is in that replicative senescence element (Telomeres), maintenance of DNA (the rest of the chromosomes beside the telomeric DNA),
and perhaps, some telomerase down the line (insects has said, have vitellogenin and mice have more telomerase in certain cells than humans (hench their teloemres being longer) - yet they die quickly - not NMRs;).
Why would NMRs die late (35 years), and are rodents, and mice, rodents too, die so quickly in 2-3 years (despite having telomerase and long telomeres).
Because of diverging goals - NMRs live in subterannean places (dark and low-O2/anoxia/hypoxia) they are 'Blind' also called 'blind mole rat' with tiny eyes/or no eyes basically as living in the dark and gaining translucid skin (no pigment, since absolutely no light UVs in darkness)).
While lab mice or wild mice in nature, live in the dark but not forever they can get out there and they live at regular 20% O2 sea-surface ambient levels; not subterranean hypoxia (5%) like NMRs.
One lives below the other lives more above. Different environment changes the morphology.
Low O2 makes for low ROS production, because O2 is needed for ROS. Low ROS = Long lifespan;
but it's more complicated than that. NMRs, like humans - who they don't live in dark caves with anoxia low O2, have advanced protective mechanisms (Redox dependent and also lipid reordering dependent as shown in the C.Elegans study; we could add even Autophagy depedent but not really,
since autophagy is a mechanism you need for 'Any' lifespan; short or long, it a necessite but it is not the Cause of extreme lifespan - it is a garbage disposer when damage happens and it can save you if your health becomes bad (as in CR activating proteasome because it 'damages' the DNA; starvation/undernutrition in CR is a 'stress' and it creates hormesis which activate both proteasome (to degrade the damage that is coming/faulty mitos); this akin to Heat Shock, Cold Shock or H2O2 stress test; all of them activate Strongly the autophagosome/proteasome).
I also liken it to short-lived temperate quahogs and long-lived polar quahogs. They are Both quahogs. One lives 5 years, the other - the same specie - lives nearly 500 years.
Something is a miss. The polar one is a state of pristing 'frozen' ...state. the temperate environment one is living the fast lane and dying in it too. The long-lived one as mitochondrial lipid reodering just like in that C.elegans. A C.Elegans living 200 days - and quahod in Iceland, living 500 years.
You can liken this to short-lived Progeria Humans who die in less than 15 years (HGPS Hutchison Gilford's Progeria Syndrome) while NMRs Rodents, Live Longer, than HGPS Progeria Humans (35 years vs 15 years). Fast aging people (diabetes or progeria or hypertension or cancer), all of them
show fast demethylation (epigenetic loss of methyl count/global demethylation in methylome and transcription loss/drifting) and of course many mitochondrial dynsfunction (OXPHOS dysfunction); and another important one is chromosomal laxing (histones are lost), the chromosomes become 'loose/loosely packed (unpacked/uncoiled))', this is seen in progeria wethere HGPS or Werner Syndrome, the lamina can't form a correct chromosome arrangment/chrosomal failure and regular instrinsic aging also displays a form of chrosomome laxing (tight/packed coiled chromosomes make from strong gene silencing (of inflammatory ones)/youth. This is again dependet of Telomeres at the end of the chromosomes)).
It seems more commonality/common grounds than we thought but differences depending species goals. That is why I hold the view inter-connected yet inter-Deconnected at the same time. It more complex than thought.
You are right there are people with diabetes and are joggers, myself I can jogg yet I carry the deadliest disease (atherosclerosis...yet another person can be obese and jogg too, they have no atherosclerosis, it's like that; that's genetics); health is mismash and very vague
to quantitize, qualitize, characterize, specify, classify and other 'ifies/ize'...
Just a 2 cents.