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Summary articles and learning goals Ageing 2019
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Learning goals task 1:1. What is ageing? Factors that affect physical ageing?
2. What is the relation between food intake and ageing?
3. What are the evolutionary theories of ageing? Related to food intake?
4. What is the selection shadow?
5. Why do we age if we can recover ourselves?
6. Could you translate the dietary findings in animals tests to humans?
Promoting health and longevity through diet: from model organisms to humans
(Fontana and Patridge)
Abstract
- Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated
diseases in invertebrate model organisms, rodents, primates, and humans.
- Meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding
improving health and function, in the absence of changes in overall intake.
- Lowered intake of particular nutrients rather than overall categories is also key, with protein
and specific amino acids playing prominent roles.
- Nutritional modulation of the microbiome can also be important, and there are long-term,
including inter-generational, effects of diet.
The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during
aging to diet and genetic variation in the response to diet are being identified. These new findings are
opening the way to specific dietary and pharmacological interventions to recapture the full potential
benefits of dietary restriction, which humans can find difficult to maintain voluntarily.
Introduction
The 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.
- Single gene mutations that extend animal life-span can ameliorate natural, age-dependent
loss of function and the pathology of aging-related diseases, including neurodegeneration.
- There is also shown that a long life is not inevitably associated with late-life disability and
disease. Specific dietary interventions can also promote long life and healthy old age.
Dietary restriction (DR) = the chronic and coordinate reduced intake of all dietary constituents
except vitamins and minerals, which was first shown 80 years ago to extend lifespan in rats. DR
improves most aspects of health during aging. Exceptions include resistance to infection and wound
healing (this rapidly improves with re-feeding).
- DR started in young, adult Rhesus monkeys greatly improves metabolic health, prevents
obesity, delays the onset of sarcopenia, presbycusis, and brain atrophy and reduces the risk
of developing and dying of type 2 diabetes, cancer, and cardiovascular disease.
- In humans, severe food restriction without malnutrition results in many of the same
physiological, metabolic, and molecular changes associated with DR in animals, including less
age-associated myocardial stiffness and autonomic dysfunction, lower core body
temperature, and downregulation of the inflammatory pathways in skeletal muscle. Humans
voluntarily undertaking long-term DR score lower than controls on multiple risk factors for
cardiovascular disease and cancer. In short-term, DR improves several markers of health.
However, severe DR with adequate nutrition (i.e. consuming at least 100% of the RDI for
each essential nutrient) is not an option for most people because it is difficult to practice and
sustain and, with inadequate nutrition, can increase the risk of impaired menstrual and
reproductive function, osteoporotic bone fractures, anemia, and cardiac arrhytmias.
,Dietary interventions that avoid unrealistic levels of self-deprivations, and pharmacological
interventions that recapture beneficial effects of DR, are therefore important goals to improve
human health during aging.
DR increases healthy lifespan in many shorter-lived organisms (figure 1).
- The experimental tractability of yeast and invertebrates facilitates discovery of the – often
evolutionary conserved – mechanisms through which genetic and environmental
intervention improve health during aging.
The mechanisms mediating the health benefits are not fully understood
in any organism. Multiple neural, systemic, tissue-specific, and cell-
autonomous mechanisms are involved. Multiple, parallel processes
contribute to the increase in health during aging from DR, and the
relative contribution of these may vary between DR regimes and
organisms. Timing of food intake, the role of specific nutrients, the
nature of the effector mechanisms, the long-term consequences of
diet, and the key role played by the gut microbiota are really
important. These findings have pointed to less drastic dietary
manipulations that could be combined with pharmacological
interventions to improve health and prevent disease during aging.
Meal frequency and timing
During evolution, many animals and humans ate only intermittently (they had no constant assess to
food). For many microorganisms and invertebrates, long periods of starvation are normal and many
of them (including C. elegans) have evolved forms of quiescence in response to the onset of food
storage. Many of the genes that control quiescence are also important in the control of lifespan.
- Interestingly, intermittent fasting (IF), with alternation of 2 days of ad libitum feeding with 2
day fasting, also extends worm lifespan. Even chronic starvation extends lifespan in C.
elegans. In rodents, both 24 hour every other day or twice weekly extends lifespan up to
30%, independent of both total food intake and weight loss. As for chronic DR, the
magnitude of the life extension induced by IF can be influenced by the age of initiation and
mouse genotype. Short term fasting (1-3 days) has been shown to protect rodents against
the damage induced by ischemia-reperfusion of the liver and kidney, by improving insulin
sensitivity, reducing expression of markers of inflammation and insulin signalling, and
increasing cytoprotective gene expression. IF can also protect against obesity, cardiovascular
disease, hypertension, diabetes, neurodegeneration and the clinical progression of several
neurodegenerative diseases. There is also found that it could be protective against cancer
progression but others say that it is promoting cancer. In human fasting in obese woman
results in reduced body weight, fat mass, and waist circumference and also reduced serum
concentrations of total and LDL cholesterol, triglycerides, C-reactive protein, and arterial
blood pressure. Also risk factors for cardiovascular disease are lowered. It could also reduce
some chemotherapy-associated side effects by protecting normal cells, but not cancer cells,
from toxicity.
- Patterns of eating over the day can also have substantial effects. Limiting daily food intake of
an isocaloric diet to a 5-7 hour time window in humans can induce health benefits compared
with a standard three to five meals per day. In fruit flies, delaying feeding until the evening
leads to reduced egg laying and causes an uncoupling of their metabolic cycle from the
central circadian rhythm. In mice the restoring of normal circadian rhythms of activity in
metabolic pathways protects the mice against weight gain, fat accumulation, inflammation,
glucose intolerance, insulin resistance, and loss of endurance and motor coordination.
Humans who eat and sleep ~ 12 hour out of phase from their habitual patterns experience
, increased blood pressure, worsening of
glucose tolerance, a reduction of the satiety
hormone leptin, and a complete inverse
pattern of the cortisol rhythm. They expect
that chronic disruption of meal patterns and
circadian rhythms, as in shift workers,
increases risk of obesity, type 2 diabetes,
cardiovascular disease, cancer, and
neurodegenerative diseases.
The molecular mechanisms
responsible for the effects of
altered meal patterns on
metabolic health are not fully
understood. There may be
compensatory changes in energy
sensing pathways, which are all
implicated in cellular homeostasis
and rhythmic oscillations of
circadian clock targets.
The profound effects of timing of food intake have hence opened a promising
avenue for interventions to improve humans’ health during aging.
Calories or specific nutrients?
There is demonstrated that a reduction in specific nutrients in the diet, rather than reduced calories
intake, is primarily responsible for improvements in health and extended lifespan, which is why we
use the term DR rather than CR. Research also shows that a restriction of protein or specific amino
acids in the diet is promoting healthspan. 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
men and woman.
In humans, little is known on the effects of dietary modifications of protein quantity and quality in
modulating molecular pathways that control aging, stress resistance, and age-associated diseases.
Rapidly accumulating metagenomic data indicate that 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.
Health, disease, and longevity on various timescales including inter-generational
The effects of nutrition, including DR, can be exerted on time-scales ranging from more or less
instantaneous to inter-generational. In mice and humans, acute responses to DR can occur, including
improved insulin sensitivity, reduced inflammation, and protection against ischemia reperfusion
injury and other surgical stressors.
Developmental programming
In contrast to immediate effects of diet, in mammals (including humans), nutrition in early life can
have lasting effects on health during aging, often referred to as developmental programming.
- For example, in rats and mouse, maternal effects on offspring which can include changes to
the composition of the egg, alterations to the environment in utero, and peri-natal effects
such as transmission of the microbiome and alterations to lactation, and can be manifest in
the offspring as changes in gene expression and epigenetic modifications, including DNA
methylation, histone modification, and expression of microRNAs, as well as evidence of
increased cellular aging.
, - In humans epidemiological data also show a consistent effect of developmental
programming by early – including in utero – nutrition, although the evidence on the
mechanisms involved is necessarily correlational rather than experimental. Changes in organ
structure and metabolism seen in humans in response to restricted nutrition – particularly
of protein – in utero can be understood as the consequences of immediate responses of the
fetus to ensure survival and spare vital organs such as the brain.
1. Viewed in this way, an under-nourished fetus makes the best of a bad job with adverse
consequences for health in later life, including reduced glucose tolerance and a higher
incidence of ischemic heart disease, problems that are greatly exacerbated by
subsequent adequate or over-nutrition.
2. However, a poor functional capacity for insulin secretion would not be detrimental to
individuals who continued to be poorly nourished and remained thin and, therefore,
insulin sensitive, and it remains possible that some fetal and post-fetal responses to low
nutrition are advantageous in conditions of continuing poor nutrition.
Inter-generational effects of diet
Current nutrition may act as a predictor of future nutritional conditions if food availability shows
local variation or if timing of natural cycles of food scarcity and abundance occurs on an appropriate
timescale. Under these circumstances, information gained early in life or even in earlier generations
could be profitably used to anticipate future nutritional prospects and adjust physiology accordingly.
This may explain why inter-generational effects of diet can also be transmitted through males.
- In drosophila, the sugar content of the paternal diet, even over a 2 day period during which
the offspring are sired, can elicit increased lipid content in offspring.
- In mice and humans, including discordant human monozygotic twins, there is a similar
signature of chromatin de-repression associated with obesity.
Evidence is also starting to point to truly inter-generational effects of diet, where information about
dietary history is epigenetically transmitted in the germline in the absence of any further input from
the organism or its environment.
- For instance, in the nematode worm Caenorhabditis elegans, starvation-induced
developmental arrest has effects that persist for at leas three generations, with the third
generation offspring of the starved great-grandparents showing increased adult lifespan. The
starvation event leads to the generation of small RNAs that are also inherited for at least
three generations, that target the mRNAs of genes involved in nutrient reservoir activity, and
that are possibly also causal in the increased lifespan of the third generation descendants.
- Effects of nutrition of the paternal grandfather on grandchildren have been reported in
humans, but the mechanisms responsible are unknown.
- Recent work with mice has suggested that sex-of-parent-of-origin effects may be much more
pervasive and influential than previously supposed. These findings could have profound
implications for human aging and disease.
Genetic variation in response to diet
Individuals of different genotypes can respond differently to diet. Such genetic effects in humans are
potentially important for identifying sub-groups that would benefit from dietary modulation.
Females and males often respond very differently to dietary and pharmacological interventions, and
evidence is mounting for the importance of other types of genetic variation.
DR has proved to extend lifespan in most species examined, including many non-model organisms,
although it has been suggested that increased lifespan in response to DR may have evolved in part as
an artefact of laboratory culture.
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