Extending Yeast Lifespan with Lithocholic Acid

A couple of interesting papers are doing the rounds, in which researchers report on a fivefold extension of yeast chronological life span through what they look on as an exercise in forced microevolution. They subjected yeast strains to an environment containing lithocholic acid, which is actually pretty unpleasant if you're a yeast cell, and allowed the yeast to adapt through generations. Few survived, and those that did survived through the acquisition of mutations that helped them resist the damaging effects of lithocholic acid. As it turns out, there is considerable overlap between mutations that help resist lithocholic acid and mutations that help resist the forms of damage that cause aging in yeast. As a result a number of the mutant lineages are stable and long-lived once the lithocholic acid is no longer present.

This is all quite interesting as a potential path to ranking the relevance of various repair and stress resistance mechanisms in cell aging, and as a way to obtain mutant lineages in which these mechanisms are enabled in potentially novel ways. Yeast are only somewhat multicellular, however, and thus one has to be careful in extrapolating information obtained on aging from yeast to animals. Since enhanced longevity through calorie restriction and cellular housekeeping mechanisms evolved very early on in the history of life, and since the underlying biological machinery is surprisingly similar in yeast and animals, yeast studies have proven very useful in understanding the ways in which cellular behavior changes in order to resist stress. There is no direct connection between cell life span and species life span, however, and when talking about yeast chronological age, it is the life span of a single cell that is under consideration.

Where the researchers overreach, I think, is in claiming that the observed outcome in microevolution argues strongly for programmed aging in macroevolution, in which aging is the result of a genetic program rather than an accumulation of biological wear and tear. It is perfectly possibly, however, to argue that their observations are in line with non-programmed aging theories in which aging is the result of damage accumulation; they have, after all, provided a way for cells to resist and repair damage to a greater degree than is usually possible through greater use of existing mechanisms. Further I'd say that the results at present are not necessarily at all relevant to the operation of macroevolution in the wild over longer periods of time, and again, the situation for single cells doesn't map directly to the situation for multicellular life.

As I understand it, there are views of the evolution of aging in which immortal species with unfettered reproduction are perfectly viable in and of themselves, but they will always be outcompeted in a changing environment by an aging species. Given the small number of mutations to produce yeast that lives five times longer than usual, why do we not see this yeast in the wild? We do not see immortals because they cannot exist, rather we do not see them because they are almost always quickly buried by their aging competitors whenever they do arise. Yet that apparently immortal animals can exist finds evidence in the absence of distinguishable aging in hydra, to pick the best known example. Even the negligible senescence observed in some species is somewhat challenging for the idea that long-lived organisms must necessarily grow more slowly and reproduce less efficiently than short-lived species.

Yeast mutants unlock the secrets of aging

The researchers exposed yeast to lithocholic acid, an aging-delaying natural molecule discovered in a previous study. In so doing, they created long-lived yeast mutants that they dubbed "yeast centenarians." These yeast mutants lived five times longer than their normal counterparts because their mitochondria - the part of the cell responsible for respiration and energy production - consumed more oxygen and produced more energy than in normal yeast. The centenarians were also much more resistant to oxidative damage, which is another process that causes aging. "This confirms that lithocholic acid, which occurs naturally in the environment, can not only delay yeast aging but can also force the evolution of exceptionally long-lived yeast."

The next step? Using yeast centenarians to test two types of aging theories: Programmed aging theories claim that organisms are genetically programmed to have a limited lifespan because aging serves some evolutionary purpose. That would mean that there are active mechanisms that cause aging and limit lifespan. Non-programmed aging theories contend that aging doesn't serve an evolutionary purpose. Therefore, an evolved mechanism whose main goal is to cause aging or limit lifespan simply cannot exist. What's more, non-programmed aging theories posit that any exceptionally long-lived organism must grow slower and reproduce less efficiently than an organism whose lifespan is limited at a certain age.

By producing long-lived yeast mutants and culturing them separately from normal yeast, the researchers were able to show that the centenarians grow and reproduce just as efficiently as the non-centenarians - thereby confirming programmed aging theories. "By confirming that there are active mechanisms limiting the longevity of any organism, we provided the first experimental evidence that such lifespan-limiting active mechanisms exist and can be manipulated by natural molecules to delay aging and improve health."

Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a three-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, three of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the three long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the three mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal, and osmotic stresses.

Our hypothesis posits the following: (1) only yeast exposed to exogenous bile acids can develop mechanisms of protection against cellular damage caused by these external stress agents and hormetic stimuli; (2) some of these mechanisms developed against bile acid-induced cellular damage can also protect yeast against damage and stress accumulated purely with age; (3) only those yeast species that have developed (due to exposure to exogenous bile acids) the most protective mechanisms against bile acid-induced cellular damage can also develop protective mechanisms against damage and stress accumulated with age; and (4) these yeast species are therefore expected to live longer. In this hypothesis, the presence of exogenous bile acids creates hormetic selective force that drives the evolution of not only protective mechanisms against bile acid-induced cellular damage but also longevity regulation mechanisms that protect against damage and stress accumulated with age. Moreover, this hypothesis suggests that yeast cells that are not exposed to exogenous bile acids cannot develop mechanisms of protection against cellular damage caused by these mildly toxic molecules. Thus, these yeast cells are unable to develop mechanisms of protection against damage and stress accumulated purely with age.

Empirical verification of evolutionary theories of aging

We recently selected 3 long-lived mutant strains of Saccharomyces cerevisiae by a lasting exposure to exogenous lithocholic acid. Each mutant strain can maintain the extended chronological lifespan after numerous passages in medium without lithocholic acid. In this study, we used these long-lived yeast mutants for empirical verification of evolutionary theories of aging. We provide evidence that the dominant polygenic trait extending longevity of each of these mutants 1) does not affect such key features of early-life fitness as the exponential growth rate, efficacy of post-exponential growth and fecundity; and 2) enhances such features of early-life fitness as susceptibility to chronic exogenous stresses, and the resistance to apoptotic and liponecrotic forms of programmed cell death.

These findings validate evolutionary theories of programmed aging. We also demonstrate that under laboratory conditions that imitate the process of natural selection within an ecosystem, each of these long-lived mutant strains is forced out of the ecosystem by the parental wild-type strain exhibiting shorter lifespan. We therefore concluded that yeast cells have evolved some mechanisms for limiting their lifespan upon reaching a certain chronological age. These mechanisms drive the evolution of yeast longevity towards maintaining a finite yeast chronological lifespan within ecosystems.

Comments

Why can't both the theories coexist is what I don't get?
Aging most probably did start off as an evolutionary advantage for uni-cellular life and was selected for.
But gradually it became less of an advantage and now we have trees that live indefinitely and humans that live for a century and more. The difference is, we are multi-cellular and very very complex.

The real question is does this have any bearing on the ways we could treat aging. And honestly I don't see much of a reason why it would. A lot of the proponents of programmed aging get caught up in very questionable research into telomeres for instance, and as far as I know, animals with extremely long telomeres that live significantly longer than a wild type counterpart are yet to be created though the idea has been circulating for decades. Maria Blasco was the last one to supposedly be working on this but it has been almost 2 years and she hasn't dropped any bombs yet.

Posted by: Anonymoose at February 1st, 2017 6:02 AM

Hi there !

''The difference is, we are multi-cellular and very very complex.''

This.

Anonymoose : you nailed it.

'' ...The next step? Using yeast centenarians to test two types of aging theories: Programmed aging theories claim that organisms are genetically programmed to have a limited lifespan because aging serves some evolutionary purpose. That would mean that there are active mechanisms that cause aging and limit lifespan. Non-programmed aging theories contend that aging doesn't serve an evolutionary purpose. Therefore, an evolved mechanism whose main goal is to cause aging or limit lifespan simply cannot exist. What's more, non-programmed aging theories posit that any exceptionally long-lived organism must grow slower and reproduce less efficiently than an organism whose lifespan is limited at a certain age. ''

''...That would mean that there are active mechanisms that cause aging and limit lifespan...''

Exactly. That is what there are going to find, that there is indeed a programmed DNA machinery at work. Programmed aging does exist and is not the sole one, damage accumulation aging coexists with it; and then interexchange.
Programmed aging epigenetically alter transcription and genes, which then manifests as terminal and irreversible damages by irreversible chemical insult reactions.
Inversely, DNA damage creates a 'Signal' DDR which triggers a 'response' to act on it (to repair it), this in turn alters transcription fidelity and can thus make epigenetic drifting (a natural process of aging - that can be reversed up to a certain point, a genome can
bounce back as it is analogically to a spring or elastic or a reed, you can bend it and stretch it a lot - but bend it/stretch it too far (damage it too much or change it too much)- and it can't get to back to its original form anymore - it becomes permanent and irreversible (translating as biophysical aging); just
like most damages, there is a threshold of ''resilience''; afterwhich surpassed it creates actual damages that are permanent and contribute to tissue/organ biological aging).

''...Non-programmed aging theories contend that aging doesn't serve an evolutionary purpose...''

I don't tink they all contend that, some do, not all; many don't. There can be an evolutionary purpose - because of/to damage accumulation (like in
mice who accumulate much damage, it's an evolutionnary 'strategy' : short-life/high reproduction/large population/rapid population mortality).
The whole point of evolution is optimal survival and adaptation under careful resources managment and under a evolutionary 'plan/strategy' (whether fed, CR or starving, the whole Insulin/mTOR thing at play),
so that the individual in a specie survives and can procreate to make it continue. That said, DNA systems are flawed, so is evolution (or let's say
it's rather the constituents/mechanisms/reactions that are flawed and that's because of entropy/thermodynamic laws having a say in this,
random errors/randomness fail are part of the nature/part of the process/errors happen and systems fail...nothing is perfect in this life, thus, flaws/lackings create opportunity
for failing/aging). It is no wonder that simple beings like hydras can live immortality, or trees near-immortally; while complex beings are mortals. Complexity
increased chances of 'problems' of 'failings'...errors, mutations, etc...instability the more complex it gets. It's a juggle and clearly, evolution,
is trying 'it's best' to 'juggle' this to 'make it work'...and make the specie survive with all their flaws. Evolution can opt a long-lived/low birthing population
or a short-lived/high birthing population strategy. So far, it seems that
the evolutionary trade-off is mortality with increased organismal complexity and inversely, immortality the more simple it gets (some cells can
be immortal...like cancers...up to a tiny animal like a hydra..that's about it). It's almost a message from evolution itself : 'Look...it's
just impossible to 'make it work' - for infinity - in an advanced/complex animal. sorry, you will perish, because you get an advantage in return : you're complex and advanced
- that's not free it has a cost, your death'.

''...What's more, non-programmed aging theories posit that any exceptionally long-lived organism must grow slower and reproduce less efficiently than an organism whose lifespan is limited at a certain age... ''

Exactly what I said earlier, but it's not necessarily a one, one thing. Sexual reproduction is costly that is certain; but speed of developmental growth is definately a Major decider.
But as was shown in many studies, there is an evolutionnary tradeoff and mechanism at play (mTOR/Insulin which connects to IGF which connect to developmental growth, which connects to glucose availability which connects to CR/starvation/specie nutrition survival determining metabolism speed
and developmental growth (more hormones or less hormones produced such as IGF, IGF-Rs in the brain, sexual ones like androgens and estrogens or food ones like ghrelin and leptin or sleep ones like melatonin or metabolistic control ones like T-3 T-4 thyroxine of the thyroid, etc)).
It is a careful balancing of all these elements that create a 'speed' of metabolism and the body that can then evolve around that; for example small dogs and bats have extremely high metabolism yet live long : evolution found ways (through UCPs, uncoupling proteins) to alter mitochondrial ROS damage and other insults - while working
around that problem of high metabolism and short life. It came with a solution : small dogs and bats systems. But these are outliers, most other animals, like mice and rats, have high metabolism and die very quickly (in 2 or 3 years...while a small dog or little brown bat can live 15 to 40 years). This means
it is a general 'trend' but not one that can't be overcomed (as shown in certain species defying these evolutionary trends - which, ironically, they, themselves, are Evolved from evolution. This means that evolution is trying to 'outdo itself' and 'its past failings'; by making certain outliers. Just like humans are. Humans
are outliers; they should be dead by 25 years old in the evolutionnary trend ladder from their mass/BMI/RMR/RMA (rate of metabolism at rest/active)...yet they live to 122. We are a pure evolution of Evolution itself, outdoing itself; and showing that certain past systems can be 'upgraded/adapted' in new ways and there are certain new tricks
that it can do by evolving it; and thus, make a human live 5 times longer.). What there seems to be and it 'holds' is that sexual reproduction is highly costly and as such the shortest lived animals are the most sexually active. This is not so much a trend though, it really is a cost of (sexual) resources on the organism.
As I stated before one study found that high gravidity women (more than 4 pregnancies had higher mitochondrial lesions then women who had no or less pregnancies), this shows that reproduction is very costly because it alters that balance between longevity resources vs sexual resources. In high reproduction the resource balance is
tipped towards sexual resources translocation; at the cost of less DNA/gene longevity/DNA repair resources (since these resources are 'used up' as sexual resources capability; rather than somatic tissue/DNA maintenance resources).

Posted by: CANanonymity at February 1st, 2017 11:45 PM

PS: it goes like that (people/animals who are sexually active - to a low degree - or the best of both (balanced), they are not sexually infertile (seen in CR/starvation) yet neither are they overfed (seen in obese/overweight/diabetes..); thus they activate mTOR to the least degree and so create less cell growth (Since mTOR activates cell growth, which is a determinant of lifespan as the cell grows it becomes senescent after a certain micron size) :

Reproduction

- CR/Starvation (famine stress/mortality)

+ Overnutrition (elevated glucose/nutrients/fats)

+ AGEs, DNA damage and carbonyls accumulation from glycoxidation/glycation

+ Insulin production for glucose disposal

+ Insulin growth factor (IGF)

+ Insulin signaling

+ Growth

+ Sexual Hormones production/Increased Sexual Activivty/Offspring

+ mTOR activation by insulin/glucose pathway

+ mTOR activating TNF-a/IL-6/p53/p16 and so forth

+ Accelerated Senescence

------------------- (Bottom Line)

Short Life

Longevity

+ CR/Starvation (famine stress/mortality)

+ Undernutrition (reduced glucose/nutrients/fats)

- AGEs, DNA damage and carbonyls accumulation from glycoxidation/glycation

- Insulin production for glucose disposal

- Insulin growth factor (IGF)

- Insulin signaling

- Growth

- Sexual Hormones production/Increased Sexual Activivty/Offspring

- mTOR activation by insulin/glucose pathway

- mTOR activating TNF-a/IL-6/p53/p16 and so forth

- Accelerated Senescence

------------------- (Bottom Line)

Long Life

Posted by: CANanonymity at February 2nd, 2017 1:49 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.