The Elixir of LifePresented by Rachel Jacob Z00-15-05-10

RLS• RLS is the yeast homologue to age in higher

eukaryotes

• Replicative Life Span (RLS) is a phenotypic characteristic

• RLS is the number of daughter cells produced prior to irreversible cell cycle arrest

• Due to asymmetric cell division

FACTORS LIMITING RLS

• Accumulation of Senescence factors

• Accumulation of Extra chRomosomal DNA Circles (ERCs)

• Damaged nuclear pore complex

• Dysfunctional Mitochondria

FACTORS LIMITING RLS

• Accumulation of cytosolic protein aggregates

• Oxidatively damaged proteins

• Vacuolar dysfunction

I n t e r v e n ti o n s p r o l o n g i n g R L S

Dietary restriction

m TOR signaling

Sirtuins

DIETARY RESTRIC TION

Reduction in nutrient availability in the absence of malnutrition.

Promotes longevity and healthy aging in organisms ranging from yeasts to humans.

Inhibition of mechanistic target of rapamycin (mTOR) through DR

D R

Reduced translation

Increased Autophagy

Effects of DR

Free radical Theory of AgingReactive oxygen species (ROS) are a family of compounds that can

Oxidatively damage cellular macromolecules which influence

lifespan. Reactive Oxygen Species (ROS) generated from mitochondrial respiration are the primary drivers of aging in humans and other species.

Autophagy

Autophagy is a cellular recycling process that can remove aged or damaged cellular components.

Autophagic activity is regulated by many factors, such as the TOR pathway, Sirtuins, and caloric restriction.

Protein Kinase A (pKA)c AMP dependent pKA pathway is a nutrient

response pathway to be implicated in lifespan extension from DR in yeast.

c AMP pathway is stimulated by the presence of Glucose.

Effects of p KA

Regulation of cell growth

Regulation of Metabolism

Improved Stress Resistance

mTOR The nutrient response pathway defined by

the mechanistic Target Of Rapamycin (mTOR).

Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies.

SIRTUINS• Sirtuins are a conserved family of (NADP)

dependent protein deacetylases.

• Sirtuins can modulate ROS which enhances lifespan for several organisms.

AMP Kinase

LOS 1Nuclear pore protein

Involved in nuclear export of pre- t RNA

Re-exports of mature tRNAs after their retrograde import from the cytoplasm

Deletion mutation extends replicative lifespan in response to caloric restriction.

Genes that affect Replicative Life Span (RLS) in Saccharomyces cerevisiae also affect aging in

other organisms such as C.elegans and Mus musculus.

“A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains

Uncovers Conserved Mechanisms of Aging”

Brian Kennedy et al. in Cell Metabolism. Published on October 8 2015

doi:10.1016/j.cmet.2015.09.008

Systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains

was performed.

Full genome-to-genome comparison demonstrated a significant conservation in

longevity pathways between Yeast and Caenorhabditis

elegans.

• Deletion of tRNA exporter LOS1 robustly extended lifespan by 60

per cent.

• Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude

Los1 from the nucleus.

Thank You!