Aging and a Clock Molecule
What does evolution tell us about aging?
all species (including unicellular organisms like yeast) have the following traits in common as they get older:
less movement
less reproduction
make less protein
less able to respond to stress
(including oxidative stress, heat shock, UV Light, etc.)
aging mechanism is likely conserved among species, as aging is central to evolution itself
therefore it's likely aging is a cellular process , as all organisms evolved from unicellular organisms
What can we learn from hormonal Changes?
they mirror this cellular process
Sex Hormone decline (less emphasis on reproduction)
Thyroid decline (less moving around)
IGF-1 decline (less emphasis on growth, less protein production)
They also help cells undergo this process
What can we learn from long lived species?
What can we learn from recently discovered long lived worms?
If you improve a worm's ability to respond to stress he lives longer (AGE-1, OLD-1, SIR2 etc. etc.)
If you slow down a worm's metabolism, he lives longer (CLK-1 etc.)
Interestingly, slowing down an organism's metabolism reduces the level of stress (including oxidative stress) an organism endures, relative to age matched controls
People:
Centarians (people who live to be over 100) have the following traits in common:
Low sugar
Low triglycerides
Low Insulin
>low sugar and low insulin implies good insulin sensitivity (the opposite of diabetes)
This means Centarians are able to use sugar more efficiently
Either they need less sugar (and hence have a lower metabolism)
Or they are able to process sugar more quickly (and hence are more able to respond to stress, including oxidative stress)
Consequently centarians have less total oxidative stress on their system, relative to age-matched controls
Comment: More evidence that aging involves a decreasing ability to respond to stress
What can we learn from premature aging diseases?
Werner's Syndrome:
Caused by a mutation in a Helicase which ends up causing a lot of mutations in the DNA of the cells of patients with Werner's Syndrome
symptoms
WS patients develop many age related diseases prematurely including arteriosclerosis, malignant neoplasms, type II diabetes mellitus, osteoporosis, ocular cataracts, early graying, loss of hair, skin atrophy.
However, not all age-related diseases are represented in WS patients. Notably absent are Alzheimer's disease and hypertension.
What we learn: DNA damage is not the cause of the aging process; if it were, WS patients would display all symptoms of premature aging
Rather DNA damage is a SYMPTOM of aging, rather than the cause
HGSN Progeria
Interesting because the condition causes decreased ability to import galactose, drastically reducing insulin sensitivity, but leaving body able to respond to other types of problems
symptoms
Most HGSN patients die from some of the same causes as the extremely aged: most from heart attacks or strokes, a few from congestive heart failure, and occasionally one or two from respiratory collapse.
bone loss
growth/sexual development
none/limited - grows normally until out of the mother, once born, problems
: mother is able to regulate child's sugar levels before it's born
Cardiac:
- Premature arteriosclerosis (one of the leading causes of fatality).
- Premature coronary artery disease.
- Angina pectoris.
- Myocardial infarction.
Congestive heart failure.
atherosclerosis
However, in spite of these problems, patients have the following things for their completely normal for their age: metabolism,hearing, vision,brain function. Also they do not get cancer at the rate the elderly do.
What we learn: Difficulties in transporting sugar (in this case galactose) are not the cause of the aging process, but rather a symptom.
What can we learn from short lived mutants?
Telomeres
So recently organisms have been produced with the inability to maintain long telomeres
If telomeres were the cause of the aging process, we'd expect these organisms to die early but they don't
In fact abnormalities aren't present until 5-6 generations or so…
What can we learn from comparing organisms?
The aging process is not mediated by cell division
For example worm (nematode) cells divide 918 times and the number of cells in their body stays fairly constant until death
Available evidence indicates that telomeres regulate uncontrolled cell division
Evolutionarily it would make sense to have two separate mechanisms for multi-cellular organisms, one which regulates cell division and one which regulates aging
Consequently it is unlikely that telomeres mediate the aging process.
So, everyone agrees that as cells and organisms get older, they are less able to respond to stress
So how does a cell know which cells to repair and keep young (ie sperm and egg cells)
And which cells it should let damage accumulate in?
Clearly there has to be some molecule "Tells" a cell how old it is
What the clock molecule governs in a cell:
Clock molecule would therefore govern the stress response (ability of each cell to respond to stress) declines with age
Reduced growth, Sexual Capacity, and movement are likely functions of this decreased ability to respond to stress
In fact if you reduce metabolism, or sexual capacity, worms actually live longer - that's why you know that reduced metabolic capacity is a symptom, rather than the cause of the aging process
Possibilities for the manufacture of a clock Molecule -
A molecule common to all species (since the aging process is likely to be common to all species)
It could be made of a protein-
It could be made of DNA
It could be made from a commonly available precursor (sugar, fat, nutrient, vitamin etc.)
The precursor would likely be something whose level is controlled anyway, for other purposes - it is likely that we are already aware of it - it would be simple