In this document you will find all the necessary answers to the learning goals in order to pass your exams. Moreover, pictures accompanying the theory are added.
- Radicals formation + inflammation
- Allocating resources for reproduction
- Micronutrients + timing
- Selection shadow is the period when selection does not play a role anymore
- Finding a model for ageing, can we frame it in a theoretical notion and different
models go around in the literature and selection shadow is one of them
- You were selected to survive, but when we become older we age and get
maladaptive consequences
Luigi Fontana > Promoting health and longevity through diet: from model organisms to
humans
Thomas B.L. Kirkwood > Why do we age?
Learning goals
Part A:
1. Is there a link between the amount of food intake and longevity?
a. Discovery that aging can be ameliorated by dietary, genetic and
pharmacological interventions has opened up the prospect of a broad-
spectrum, preventive medicine for aging-related diseases.
b. However, severe DR with adequate nutrition is not an option, because it is
difficult to practice and sustain.
c. Individuals of different genotypes can respond differently to diet > identifying
sub-groups that would benefit from dietary modulation is the way to go
d. DR may have evolved in part as an artifact of laboratory culture, but in
general the lifespans of model organisms show a tent-shaped response to the
level of food intake, with peak lifespan at intermediate food intake and a
decline through starvation to the left and through increased levels of food
intake to the right.
2. Difference in influence of caloric restriction in ageing between species?
a. Dietary restriction (DR), implemented as chronic and coordinated reduced intake of
all dietary constituents except vitamins and minerals, was first shown 80 years ago to
extend lifespan in rats.
b. 30% of DR animals dying at old ages without gross pathological lesions, compared
with only 6% of ad-libitum-fed controls
c. DR started in young, adult Rhesus monkeys greatly improves metabolic health
d. Dietary restriction:
1. C. elegans & drosophila and mice > neural circuits both detect nutrient
status and control the responses to it > the levels of metabolites, the
activity of the nutrient sensing insulin/igf signaling network
2. C. elegans, steroid hormone signaling and growth hormone in the
mouse
3. Enhanced genomic stability and chromatin remodeling improved
chaperone-mediated protein homeostasis and cellular turnover
processes
, 4. Inhibition of AKT activates FOXO (transcription factor) upregulating
several longevity pathways controlling DNA repair, autophagy,
antioxidant activity, stress resistance and cell proliferation
5. Inhibition of mTORC1 improves proteostasis, increases autophagy
and enhances stem cell function
6. Systemic or tissue-specific overexpression of some sirtuins also
increases genomic stability reduces NF-kB signaling and improves
metabolic homeostasis through histone deacetylation
7. Activation of SIRT1 and AMPK activates PGC-1a transcriptional
regulator of mitochondrial function, antioxidant defenses and fatty acid
oxidation
8. Heat shock factor 1 and Nrf2 upregulate transcription factors HSP70,
p62 and ATF3 and induces several antioxidant and drug-metabolizing
enzymes that prevent the age-dependent impairment of proteostasis
and promotes the maintenance of cell structure, redox and
intermediary metabolism
e. Maternal effects on offspring can include changes to the composition of the egg,
alterations to the environment in utero and perinatal effects via expressed as
changes in gene expression and epigenetic modifications, but evidence on the
mechanisms involved is necessarily correlational rather than experimental
f. Thrifty phenotype hypothesis = many changes in organ structure and metabolism
seen in humans in response to restricted nutrition (protein) in utero can be
understood as the consequences of immediate responses of the fetus to ensure
survival and spare vital organs, but some fetal and postnatal responses to low
nutrition are advantageous in conditions of continuing poor nutrition.
g. Intergenerational effects of diet can also be transmitted through males via epigenetic
inheritance, but evidence is largely correlational:
- Drosophila, the sugar content of paternal diet can elicit increased lipid content
in offspring
- Mice and humans similar signature of chromatin de-repression associated
with obesity
- Mice subjected to in utero undernourishment are glucose intolerant and can
transmit the glucose intolerance even though they themselves are not
undernourished > sperm DNA hypomethylated at multiple sites and
information about dietary history is epigenetically transmitted in the germline
- C. elegans starvation-induced developmental arrest has effects that persist
for at least three generations > generation of small RNAs which target
mRNAs of genes involved in nutrient reservoir activity > seen in paternal
grandfather on grandchildren in humans
h. Under conditions of high larval density and low food availability, larvae develop into
the alternative, non-feeding, non-reproducing third instar called a dauer and improve
into adulthood when normal conditions get back > preservation of full adult longevity
after even an extended dauer period indicates that the effect is not entirely due to
reduced metabolism
a. Works for lab rats but also for humans
- In humans, severe food restriction without malnutrition results in many
of the same physiological, metabolic and molecular changes
associated with DR in animals: less age-associated myocardial
, stiffness and autonomic dysfunction, lower core body temperature,
and downregulation of the pi3k/akt/foxo and inflammatory pathways in
skeletal muscles.
- Long-term DR score lower than controls on multiple risk factors for
cardiovascular disease and cancer and short-term improves DR
several markers of health.
- In overweight or obese premenopausal women showed that fasting for
2 non-consecutive days results in reduced body weight, fat mass and
waist circumference and lowered biomarkers for cardiovascular and
cancer.
- Short-term fasting prior to chemotherapy reduces some chemotherapy
associated side effects
- Humans who eat and sleep 12 hr out of phase from their habitual
patterns experience increased blood pressure, worsening of glucose
tolerance, a reduction of the satiety hormone leptin and complete
inverse pattern of the cortisol rhythm
- Overweight obese and lean women with PCOS randomized to earlier
meal timing lost more wieght displayed higher insulin sensitivity, lower
serum testosterone concentration and increased ovulation rate than
controls eating isocaloric diets with later meal pattern
- In humans unlike rodents chronic severe calorie restriction does not
reduce serum IGF-1 concentration unless protein intake is also
reduced suggesting that dietary protein or specific amino acid intake
may be as or more important than calorie intake in modulating IGF-
related biological processes and disease risk
- In humans little is known on the effects of dietary modifications of
protein quantity and quality
- It seems that even short episodes of DR early in adulthood in male
mice can induce a glycemic memory apparent as increased glucose
tolerance, however in mice and humans acute responses to DR occur
including improved insulin sensitivity, reduced inflammation, and
protection against ischemia reperfusion injury and other surgical
stressors.
3. Does the type of food make a difference?
- Dietary composition even for just 3 macronutrients with so many possible
combinations is difficult to study and dietary composition can also affect
overall food intake and its timing through effects on hedonistic value and
satiety and further complicate analysis
- Effects of diet on health may also be age specific
- Macronutrients >
a. Reduced intake of calories, rather than of specific macronutrients was
considered important for health benefits > 40% of calorie restriction,
but not 40% protein restriction increased lifespan
b. However, protein-restricted rats were not food restricted, because
their growth rate was normal
c. Reduction in specific nutrients in the diet is primarily responsible
- Protein and amino acids >
, a. High protein intake, especially from animal sources rich in essential
amino acids for combating obesity, sarcopenia, osteoporosis, frailty,
surgical stress and mortality, however accumulating evidence points
instead to restriction of protein or specific amino acids in the diet as
promoting healthspan
b. Drosophila, restriction of protein-containing yeast, but not
carbohydrate or energy extends lifespan
c. Adding back essential amino acids to the diet of DR flies decreases
lifespan
d. Mice median lifespan progressively increases up to 30% as the dietary
protein-to-carbohydrate ratio is decreased
e. Dietary protein intake is an important regulator of the IGF-1/mTOR
network
f. Isocaloric restriction of protein and substitution of plant for animal
proteins markedly inhibit prostate and breast cancer growth in human
xenograft animal models
g. Selective restriction of asparagine, glutamate or methionine in medium
extend lifespan in yeast and in drosophila and rodents for restriction of
methionine and tryptophan
h. DR rhesus monkey, the Wisconsin diet contained higher
concentrations of methionine and branched-chain amino acids than
NIA diet > explain differences in effects on cancer and mortality
i. mTRO activity is modulated by different essential amino acids with
branched-chain amino acids playing a key role > no individual amino
acid available than GCN2 is activated which stabilizes ATF4 a
transcription factor for integrated stress response
j. Trans-sulfuration pathway lesions (sulfur containing amino acids as
methionine are metabolized via here) result in pathologies during
aging and in mice higher activity of this pathway increased health
during aging
- Microbiota-derived factors and healthy aging >
a. Altered food intake, especially protein and insoluble fiber, have rapid
and profound effects on gut microbiota structure, function and
secretion of factors that modulate multiple inflammatory and metabolic
pathways
b. Diet-induced microbiota dysbiosis is associated with increased risk of
developing cardiovascular disease, obesity-associated metabolic
abnormalities, cancer and autoimmune and allergic disease
c. Vitamin B12 influenced patterns of gene expression and the rate of
development and fertility of the worm
a. Intermittent fasting (timing of food)
- Many of the genes that control quiescence (response to the onset of
food shortage) are also important in the control of lifespan
- Extends worm lifespan involving small GTP-ase RHEB-1 and
insulin/Igf signaling
- In rodents, both fasting for 24 hr every other day or twice weekly
extends lifespan up to 30%
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