Diversity of Aging Across the Tree of Life Alex K. Chen Feb. 28, 2014.

Diversity of Aging Across the Tree of Life

Alex K. ChenFeb. 28, 2014

The Hype

• Is any of this right???

http://www.cracked.com/article_20055_6-unassuming-animals-that-are-secretly-immortal.html

How do we measure aging, exactly?

Basically: aging is imbalance between “damage” and “repair”. Basic ways to measure damage:• Lipofuscin accumulation (from the oxidation of unsaturated fatty acids)/lipid

peroxidation• Accumulation of damaged proteins (carbonylated proteins), many by ROS• Nuclear DNA damage• mtDNA damage• Telomere attrition

Newer ways of quantifying aging (not necessarily damage, but information loss):• Systems Biology theory of aging (how some proteins correlated at young ages

can become anti-correlated at older ages).• Metabolome/transcriptome/epigenome changes with age

Questions to *always* ask for each species

• What do they ultimately die of?• Even if they have regenerative capacity (or can elongate their

telomeres), do they still accumulate damaged lipids/proteins/DNA? If so, they are still aging.

• Even if an organism has the regenerative capacity to live “indefinitely”, can its information be preserved “indefinitely” too? (I’m not talking just about information contained in the DNA, but also information contained in the arrangement of proteins and cells in the organism [especially relevant in the organism’s brain])

• Do any individual cells in the organism live as long as the organism does?

How general is aging?• Bacteria• Plants• Simple animals without a high level of cell differentiation (e.g.

hydra)• Complex animals with higher levels of cell differentiation• Cold-blooded vs. warm-blooded organisms. While macaws and

bowhead whales have amazing lifespans, is it possible for any of them to reach the simple quahog clam’s lifespan?

How many levels of explanation?Evolutionary level of explanation (selection pressure)Mechanistic level of explanation (hardcore biochemistry)

Do bacteria age?• Thomas Nystrom 2007• Asymmetrical accumulation of damaged proteins by the mother cell

(so damaged proteins don’t accumulate in all bacteria)• Selection-Mutation balance (to take care of DNA mutations). Maybe

this is easier to do in low parental investment organisms that can reproduce extremely quickly

• Couldn’t mitochondria do this too? (especially the mitochondria of exercised-individuals)

Diversity of Aging Across the Tree of Life (Jones et al. 2013)

Where are Naked Mole Rats??

• Little evidence of senescence in many non-mammal species (by the time survivorship curves reach 0)

• Gompertz Curve of Mortality does not seem to apply for many non-mammals.

• So then why don’t we see an increase in the hazard ratio/death rate with time?

Why Study Long-Lived Organisms?

• Healthspan vs. Lifespan. Better elucidating this could explain a lot.

• Which of their metabolic adaptations are ubiquitous in all long-lived organisms? Which are specific to just one of them?

• Is it reduced ROS? Enhanced defenses against ROS? Enhanced autophagy? Reduced accumulation of lipofuscin? Elongated telomeres? Or all of the above?

• How much does level of cellular differentiation matter?• We’re now in the era of the genome,

epigenome/proteome/transcriptome. So this is the era of promising discoveries.

Interesting case studies of long-lived organisms

• Naked Mole Rats: Numerous. cell membranes have 9 times less DHA (a PUFA) than mice, cancer-resistant, more efficient autophagy, cysteine-enriched proteome

• Ocean quahog (Arctica islandica): Less endogenous ROS production (but does not have enhanced antioxidant capacity). Ungvari et al. 2011

• Birds: leak fewer free radicals from their mitochondrial respiratory chain (don’t need as many antioxidants) despite much higher metabolisms

• Lobsters can live 140+ years, and have indeterminate growth (like all decapod crustaceans). Fitness can increase w/age because larger lobsters can accumulate more eggs. But accumulating neurolipofuscin is used to quantify their age (Maxwell et al. 2007)

• Turritopsis dohrnii can revert to a sexually immature, colonial stage after sexual maturity (isn’t this like reprogramming adult stem cells? Is there anything to eliminate accumulation of lipofuscin/damaged proteins?)

• Hydra vulgaris (see Martinez et al. 2012). FoxO gene might have protective role, and is inhibited by insulin/IGF1.

• Planarians (asexual planarians don’t have telomere erosion [Tan et al. 2012]). A lateral fragment 1/279 th the size of the original worm can regenerate the entire worm. They have neoblasts constituting 25-30% of all planarian cells (but do those accumulate any damage?)

• Turtles (very unusual physiology). Freshwater turtles can survive for hours without oxygen. “The liver, lungs, and kidneys of a centenarian turtle are virtually indistinguishable from those of its teenage counterpart” – Chris Raxworthy.

• Rockfish (though Guerin’s research seemed to stop in 2004).

Is information lost through the mechanism that the organism uses to protect itself against aging?

• In the “immortal” jellyfish, planarians, bacteria, and plants, I would probably say yes (do they also pretty much operate by selection-mutation balance?).

• Clams and lobsters: probably more ambiguous case (differentiated tissue, but not especially complex)

• But in the case of vertebrates (turtles, bowhead whales, Andean Condors) probably not.

We’ve only explored a small fraction of this!

• Can’t we explore more of the diversity?

Other interesting animals

• Axolotl (amazing regenerative capacity), but maximum lifespan ~25 years

• Hibernating animals• Deepwater fish (like coelacanths)• Echinoderms (have any studies been done at

all?) What about the LCA of echinoderms and vertebrates?

• Tardigrades!• Non-(C. elegans) nematodes

Some extra questions• What *do* invertebrates die of, anyways? Would humans die like invertebrates do if heart disease, cancer, stroke,

Alzheimer’s, and all the other major killers of age did not exist?• Do anaerobic bacteria accumulate damaged proteins/lipids at a lower rate than aerobic bacteria? • How do we quantify loss of healthspan from lipofuscin/protein damage in simple organisms like yeast?• Do stem cells accumulate damaged proteins/lipids/DNA at a lower rate than other cells?• Does the asymmetric accumulation of damaged proteins seen in bacteria apply for multicellular organisms? E.g.

could mitotic cells undergo mitosis, have one of the two cells accumulate more of the damage, and have that damaged cell undergo apoptosis?

• For plants with lifespans of thousands of years: do any of their individual cells live for thousands of years? Or does their “living layer”/meristem expand outwards as the inner part die? What do plants do with carbonylated proteins? Also, what is the background rate of protein carbonylation in the interior of the tree? (plants don’t have many lipids to oxidize). How many sugars do their interior cells need?

• How much damage happens to the extremely-long lived proteins in the bowhead whale proteome? Do they accumulate more damage to them by time of death than, say, shorter-lived organisms?

• Far-fetched: (could hard-to-quantify differences in the spatial-temporal distribution of damage/repair be the only way to really learn the answers to all of our questions for sure? [mitoflashes are a promising step in this direction])

If you want to learn more

• Steve Austad• Daniel Promislow• http://www.agelessanimals.org/ (inactive

since 2004)• http://genomics.senescence.info/species/