THE METHUSELAH COCKTAIL - MAX-PLANCK-GESELLSCHAFT
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The fruit fly Drosophila
melanogaster only grows
to a size of two to three
millimeters. Scientists use
a brush to separate individ-
ual insects with differing
characteristics.
Pho t o: F r a n k V i n k e n
56
The Methuselah
cocktail
Text: Kl aus Wilhelm
Max Planck Research · 1 | 2020
Knowledge
From
Biology & Medicine
Linda Partridge and her colleague
Sebastian Grönke at the Max Planck
Institute for Biology of Ageing in
Cologne can’t promise eternal life – but 57
they are at least discovering ways to
lead a healthier one. The researchers’
findings in fruit flies and mice have In addition to a daily dose of rapamycin, ing how cells, tissues, and organisms
their food contains two other drugs: age. She now heads research teams at
revealed astonishing new insights into lithium, known as a mood stabilizer the Max Planck Institute in Cologne
aging that will also benefit us humans. to treat depression, and the drug tra- and at University College London.
metinib, which is used to treat can- Numerous biological mechanisms
cer patients. “The triple cocktail ex- are conserved across species, and
tends the usual lifespan of the fruit that’s why scientists usually perform
The fruit flies of Sebastian Grönke that flies by almost 50 percent,” explains research on flies and mice. “Time
made it into the tubes marked “Rapa” Linda Partridge, who heads the De- isn’t on our side; life expectancy is
have won the lottery. They reach an partment of Biological Mechanisms continuing to rise in many west-
age of two months – an advanced age of Ageing at the Max Planck Insti- ern industrialized countries,” Par-
for flies – and are still fit and healthy. tute in Cologne. The drugs have en- tridge says. It has been calculated
“Rapa” stands for “rapamycin”, a drug abled some of the insects to live for that in 2060, there will be more than
that’s one of the most promising anti- as long as four months – the highest ten million people over the age of 80
aging substances of our time. age ever attained through the admin- living in Germany. Every fifth baby
istration of drugs. Typically, the flies born today could live to be 100.
Flies exposed to rapamycin – up to now die between two and three months
prescribed as an immunosuppressive of age. When it comes to aging, genes only play
drug following kidney transplant – a minor role. “Their contribution to
don’t just live considerably longer, On the strength of such results, life expectancy is less than 20 per-
they also stay healthier. The Max Partridge is optimistic that such ad- cent – perhaps even less than ten,”
Planck researchers can measure such vances will also enable humans to re- the biologist explains. Environmen-
improvement by means of a specially main generally healthy into very old tal factors, individual behavior, and
devised fitness test for flies: “When age. “We won’t be able to do away a person’s social and economic status
rapamycin is added to their food, with death,” she says, “but we can are far more important. Unhealthy
they still perform at the same level at certainly reduce illness and infirmity habits such as overeating, seden-
60 days old as they did when they in old age.” Her life as a researcher tary lifestyle and smoking have been
were young,” Grönke explains. has mostly been devoted to unravel- proven to reduce life expectancy.
Max Planck Research · 1 | 2020knowledge from
Experiments on different animal spe- flies fed on a diet with less protein
cies are continually revealing new live longer. And this comes at the
ways in which the biological clock cost of reduced growth and lower
can evidently be turned back. Two fertility.
years ago, for example, a discovery by
Dario Valenzano, a colleague of Par- The scientists, however, wanted more
tridge at the Institute, caused a stir. detailed information. “Our re-
He had found that fish fed micro- sults show that not all amino
organisms from the guts of younger acids are equally important. Essen-
fish of the same species live longer. tial amino acids such as leucine, iso-
In another study, colleagues in the leucine, or valine are particularly
Pho t o S: F r a n k V i n k e n
U.S. discovered that replacing the important for longevity,” Grönke
blood plasma of older mice with that explains. Essential amino acids are
of younger animals had an astonish- those that the body can’t synthesize
ing effect on the aging process. itself; they have to be ingested with
food. They regulate a signaling path-
In many animals, exercise and diet are way known as “TOR,” which is in-
the primary factors influencing the volved in important aging processes
speed of aging. Mice that are allowed in cells.
to consume only 60 percent of their
normal diet live considerably lon- The researchers observed the same phe-
ger and remain healthier than mice nomenon in mice. One study has re-
fed a standard ration. Rhesus mon- vealed that consuming lower quanti-
keys have also been to live longer ties of certain essential amino acids
58 under dietary restriction when the can actually have a positive effect on
diet contains sufficient quantities health – including in humans. Howe-
of vitamins and minerals. In recent ver, it’s still unclear whether this also
years, however, Partridge and her results in longer life. The scientists
team have come to suspect that the also used the genome information of
key to living a longer and health- the fruit flies to define their dietary
ier life into old age isn’t calorie re- amino acid requirements. “This al-
striction; instead, it’s the particular lowed us to develop a specialized diet
nutrients in an animal’s diet. It is for fruit flies that contains neither
eating too many of these, they sug- too few nor too many amino acids,”
gest, that will reduce life expectancy says Grönke. “Animals fed this food
and increase the risk of age-related feel full earlier and therefore eat less.
The fruit flies in Linda Partridge’s
diseases. Nevertheless, they grow faster, be- and Sebastian Grönke’s laboratory live
come larger, and lay more eggs than in finger-length tubes sealed with a
In the laboratory, Sebastian Grönke other fruit flies fed with standard gas-permeable stopper.
points to an ordinary-looking shelf food. And, despite this, they live just
lined with dozens of cans. These as long,” Grönke explains.
contain chemicals for the flies’
food. In a time-consuming process, Reducing the quantity of essential
Partridge’s colleagues in London de- amino acids has an impact on a net-
veloped a fly food with a chemically work of cellular signaling pathways
defined formulation. This allows the known as the “IIT network.” This
scientists to modify the diet of the network is active in a wide range of
flies at will. This enabled Grönke organisms, from fruit flies to hu-
to discover which nutrients pro- mans, and controls development,
long lifespan and improve health in cell proliferation, growth, reproduc-
old age. Fruit flies fed on a diet high tion, and the stress response. The
in protein and amino acids die ear- network includes “insulin/IGF-1”
lier. To compensate, the insects lay and “mTOR” signaling pathways,
a large number of eggs. Conversely, each with a large number of differ-
Max Planck Research · 1 | 2020Biology & Medicine
Fitness test for flies: only
physically fit flies can climb
up the tubes quickly. When
the first ones have reached
the top of the left-hand tube,
the upper section is moved to
the right, and the next round
begins. Gently tapping the
tube sends the flies back to
the bottom and then they have
to repeat their climb to the top.
This procedure is repeated
five times, until the fittest
flies have reached the far right
section.
59
ent signaling molecules, the most individual substance extends the study in the U.S. involving several
important of which are IGF-1 and longevity of the flies by an average thousand participants. People who
mTOR. Flies and mice that have the of eleven percent. A combination of are unable to prolong their lives even
modified genes for these molecules two of them increases life expectancy with optimal nutrition could bene-
age more slowly and become genuine by around 30 percent, while all three fit from such drugs. Most of us, af-
Methuselahs. Like a precise sensor, increase life expectancy by nearly 50 ter all, find it difficult to stick to a di-
the IIT network measures the nu- percent. At the same time, they com- etary regimen for decades on end.
trient status in the body and adjusts plement each other when it comes to
metabolic processes as required, reducing side effects. Rapamycin on The researchers have also searched for
based on the demand for and avail- its own induces adiposity, while lithi- other anti-aging candidate drugs.
ability of food. Reduced food con- um appears to negate this. They trawled through a database of
sumption evidently puts a brake on active agents with known effects and
the activity of the network. Drugs that can slow down and promote performed computer simulations to
healthy aging, it seems, are no longer find out whether these bind signal-
The drugs lithium, trametinib, and a mere pipe dream. Metformin, used ing molecules in the IIT network.
rapamycin also have an effect on va- to treat diabetes, is another possibili-
rious signaling molecules of the IIT ty. Its impact on life expectancy will They soon discovered what they were
network, reducing its activity. Each soon be investigated in a large-scale looking for. A drug known as tane-
Max Planck Research · 1 | 2020knowledge from
spimycin had already proven its po- “mitochondria”, the power genera- and measured the impact on life ex-
tential in the model organism most tors of the cell, and, this was also suf- pectancy. In the young animals, the
frequently studied by researchers on ficient to extend the lifespan of the results were as expected. The mice
aging: the nematode Caenorhabditis animals. The IIT network therefore on a restricted diet lived to a very
elegans. It blocks the heat shock pro- controls various life-extending pro- old age and were still comparatively
tein Hsp90 and reduces the number cesses in different tissue types. healthy even at an advanced age. In
of “senescent cells.” These are ma- contrast, animals fed a restricted
ture cells that increase in number in diet only later in life experienced lit-
old age and emit substances that fa- tle or no benefit.
cilitate chronic infection. As a result,
they contribute to diseases associ- Analyzing gene activation in various
ated with old age, such as heart at- tissues showed that the liver adapted
tack and cancer. In young people, the quickly to the new diet. By contrast,
immune system removes these cells. in adipose tissue, the researchers ob-
In the elderly, however, they are pro- served a memory effect of the previ-
tected from destruction by precisely SUMMARY ous diet. Activation of fat metabolism
the Hsp90 protein. genes in the precursor cells of the
The IIT network has a major actual fat-storing, adipocyte cells
impact on how organisms age.
Tanespimycin is associated with severe Pharmacological and genetic can be influenced by lifestyle in
side effects, however, and needs to be inhibition of this cellular youth, but not later on. As a result,
administered with caution. “Even so, signaling network results in the mice that only began to fast later
it might be feasible to combat old increased life expectancy. in life did indeed lose weight, but the
age-related diseases with short-term Dietary restriction and genes in the adipose tissue remained
localized administration, such as reduced consumption of active at a similar level to that of ani-
60 in cases of macular degeneration of essential amino acids mals with a normal diet. In addition,
the eye, the commonest cause of age- decrease the activity of the the changes in the composition of
IIT network. Fruit flies
related blindness,” Partridge ex- and mice therefore live
lipids in old mice were less marked.
plains. This prompted the resear- longer in laboratory tests The various lipid molecules have
chers to investigate whether drugs tar- when they are given a different functions: triglycerides,
geting the IIT network might delay restricted diet. for example, are used by the body to
aging throughout the body, even store fat, phospholipids are compo-
A combination of rapamycin,
though they are activated only in cer- lithium, and trametinib nents of cell membranes, and choles-
tain tissues. They analyzed whether significantly increases the life terols act as signaling substances.
the brain, muscle, gut, and adipose expectancy of fruit flies.
tissues of a fruit fly produce the same The drugs also reduce acti- Adipose tissue therefore has an impor-
vity of the IIT network.
proteins when the IIT network is less tant part to play in the body’s
active. “That clearly wasn’t the case, The adipose tissue possesses aging process. There, dietary habits
as we discovered. The various cell a type of memory for environ- chiefly affect the mitochondria. If
types respond differently,” Partridge mental influences and life- the animals consume less food, these
style. For this reason, dietary
explains. Of the 6,000 proteins stu- modification in mice only cellular power generators are pro-
died, 2,400 are synthesized at differ- extends life expectancy if it is duced in greater numbers – but only
ing levels in the brain, muscle, gut, implemented at young age. if the animals eat less early on in life.
and fat. The gut, for example, pro- In the case of mice, “early on” means
duces more enzymes that control the after just a few months, as a further
quality of protein synthesis when the study by the researchers in Cologne
IIT network is less active. has shown. This memory effect may
be based on “epigenetic” alterations
“That local factor alone can prolong of genes, in which DNA is tagged by
an organism’s overall lifespan,” small molecular groups, switching
Partridge explains. On the other External influences also have varying genes on or off. In this way, environ-
hand, if the IIT network is sup- effects on different tissue types, de- mental factors can have a relatively
pressed in a fly’s fat tissue, entirely pending on age. For example, the rapid impact on genes, and their ef-
different proteins are synthesized. Max Planck researchers put young fects can even be passed on to the
These improve the quality of the and older mice on a restricted diet next generation.
Max Planck Research · 1 | 2020Biology & Medicine
Probability of survival
in percent
Maximum lifespan
of a fruit fly 98% 84% 64% 54% 28% 14%
ALL
Rapamycin 100% 98% 90% 72% 62% 48% 20%
ALL
Lithium 100% 99% 98% 82% 62% 48% 20%
Gr a ph ic: G CO M e di e nage n t u r
ALL
Trametinib 100% 99% 97% 83% 72% 56% 30%
ALL
Combination of rapamycin,
lithium, and trametinib 100% 100% 100% 100% 98% 95% 82% 21% 18%
ALL
30 40 50 60 70 80 90 100 110 120
Lifespan in days
61
Studies in the U.S. have shown that that anyone who wants to live a long to employ these biomarkers in age
some epigenetic changes are age-re- time needs to start early. “Our re- research on animals and in clinical
lated. On the basis of around 350 search shows that such dietary hab- studies on humans. However, blood
such DNA modifications, scientists its need to be adopted at an early age. biomarkers may eventually help
can determine the biological age The foundations for a healthy old age young people find out, with a high
of a person with astonishing accu- are already laid in early adulthood,” degree of certainty, whether they
racy. The epigenetic clock ticks at Linda Partridge explains. will suffer from certain illnesses
the same pace in all the cell types in old age. Then everyone would
studied – whether in cells that are A further discovery made in the labo- be able to decide for themselves
continuously being regenerated or ratory by the researchers in Cologne whether they should exercise more
in those that originally developed might offer an incentive to start and eat a healthier diet, or whether
in the embryo. The precise impact thinking about your own aging pro- they should even take preventive
of these DNA modifications is still cess early on. medication to improve their health
unknown. in old age.
Together with colleagues from Leiden
Dietary restriction clearly has an effect University Medical Center in the
on age-related epigenetic changes. Netherlands, they took blood sam-
It also stimulates lipid metabolism ples from tens of thousands of people
reprogramming. This protects the and searched for molecules that indi-
body from the harmful effects of cate the remaining lifespan a person
fat deposition in the liver, as well is likely to have. Following exten-
as against insulin resistance – a sive analysis, the scientists identified
typical sign of age-related, type-2 14 biomarkers, including various
diabetes. amino acids, the ratio of “good” to
“bad” cholesterol, fatty acids, and
If the results of the studies on mice are signaling molecules involved in in-
transferred to humans, it is clear fections. Initially, the scientists aim
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