Figuring out how restricted diet increases lifespan

Education, Engineering, Science, Research,

Bengaluru, September 17 : The traditional dictum ‘eat
less, live long’ is well known. Scientists are now trying to figure out if this
indeed works at the cellular level.

A
preliminary report by a team of Indian scientists has explored how restricted
diet affects molecular mechanisms
leading to prolonging lifespan and
delaying age-related diseases. They have conducted experiments in nematodes
(worms).

These
studies indicate that dietary restriction influences the functioning of the ‘endoplasmic
reticulum
’, training it to effectively mount a stress response when
overloaded with unfolded proteins. This results in degradation of unwanted
proteins, thereby preventing the building-up of toxins which in turn translates
into longevity of the cell.

Endoplasmic
reticulum is a cell structure that participates in synthesis and modification
of amino acid chains into functional proteins within the cell. Glucose
molecules play a significant role in helping it to carry out the protein
folding process.

When
diet is restricted, there is inadequate glucose level which triggers mild
stress in endoplasmic reticulum due to increased load of unfolded proteins. It immediately
responds by improving its machinery to clean up misfolded proteins to reduce
cell toxicity.

As
we age, there is an increase in misfolded proteins due to natural deterioration
of endoplasmic reticulum, contributing to ageing and age-related diseases like
Alzheimer’s.

“A
restricted diet from an early age primes endoplasmic reticulum to gear up to
perform better and achieve hormesis — the process by which a small amount of
stress reprograms a cell to resist acute stress at a later stage. This
memorised condition prevails at an advanced age also, thereby preventing
age-related disorders and increase in life span,” explained Dr Arnab
Mukhopadhyay from the New Delhi-based National Institute of Immunology, who led
the research, while speaking to India
Science Wire.

The
team observed the growth patterns in two groups of worms: one was given a
restricted diet, while the other group had free access to food.  It was observed that worms fed on a restricted
diet had a
better ability to maintain healthy endoplasmic reticulum and showed a
30-40%  increase in lifespan compared to
the other group.

By using a mutant worm that gulps
food at much slower rate compared to wild-type, the team observed that slow
food consumption led to a dramatic increase in longevity and better health in
the worm. 

Since it is difficult to
comply with a strict diet regimen in practical life, the group explored the
possibility of a drug that could mimic a restricted diet condition. For this, a
readily available chemical called tunicamycin was fed to worms without any
dietary restrictions. The chemical was exposed to worms briefly during their
early stages of development. Also, a
fluorescent reporter gene was introduced in the worms to map the exact
happenings at the cellular level.

It was found that the chemical
in small doses blocked the availability of glucose and its derivatives for the
endoplasmic reticulum proteins preventing their proper folding. It acted like a
priming agent on cell structure, inducing mild stress in worms. The worm’s
lifespan increased by about 20%, indicating that the molecule produced an effect
similar to diet restriction condition.

“Our
study opens the possibility of using endoplasmic reticulum-targeted
pharmacological interventions to mimic the longevity and health effects of
dietary restrictions. A small dose given early in life can prime the structure
to function better in adult life,” said Dr Mukhopahyay.  More animal studies are being planned now.

The
research team included Latika Matai, Gautam Chandra Sarkar, Manish Chamoli,
Yasir Malik and Umanshi Rautela (NII); 
Shashi Shekhar Kumar and Nihar Ranjan Jana (National Brain Research
Center); and Kausik Chakraborty (Institute of Genomics and Integrative Biology).
The results were published in the journal PNAS

By Susheela Srinivas  

(India
Science Wire)

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