Note: Protecting the aging genome

มาดู theme ของการเข้าสู่สังคมผู้สูงวัย

Note: Protecting the aging genome

doi: 10.1016/j.tcb.2019.12.001

Three main layers protect the accumulation of DNA damage

• Reducing damaging molecules (antioxidant)

• Repairing DNA damage

• Inducing senescence/apoptosis to response to persistent DNA damage

The end of this paper -- help to propose novel interventions which increase healthspan!!

DNA repair is quite conserved and important for living organisms as stated above.

Markers of DNA damage - observe in age-associated disease

Obvious evident -- ppl who has defective in DNA repair -- show features of premature or accelerated aging

Defect in different pw --aging features in different tissues;

• Cockayne syndrome, ataxia-telangiectasia -- premature neurological aging

• Werner syndrome, Hutchinson-Gilford progeria -- cardiovascular aging

>50 DNA repair disorders described with various degrees of overlapping phenotypes with aging -- > suggest different types of DNA damage -- > different pathologies in aging

Most common oxidative DNA lesion -- mutagenic 8-oxoguanine -- > accumulate in several tissues with age

ss and db strand DNA break -- activates  PARP1 -- activity of this enzyme increase with age -- >strand break accumulate in elderly

DSB markers; 53BP1 and gH2AX -- increased with age across multiple tissues and in senescent cells

Consequences if DNA is left unrepaired

Three outcomes; but altered with age

1. Cell transform and become cancerous

2. Entering non proliferating state (senescence)

3. Die through apoptosis

Cell death

Apoptosis

• With age, apoptotic activity changes

• Heart, kidney, skeletal muscle, and T cell

• Increased apoptosis -- contributing to loss of cellularity (causing increased production of free radicals) but it helps to prevent the accumulation of mutation in DNA 

• Colon

• Apoptosis -- decrease with age

Parthanatos

• DNA damage is central to its initiation

• Activation of DNA damage responder PARP1 -- formation PAR polymers -- activation of apoptosis -inducing factor + caspase-independent cell death

Cell senescence

If a cell invades death on DNA damage -- > usually cells enter senescences. Several ways to induce senescence;

• Replicative senescence in somatic cells

• Oncogene-induced senescence

• Excessive DNA damage

Younger age -- senescence helps

• Tumor suppression

• Wound healing

• Tissue development

Drugs that clear the senescence cells ~ senescences have been believed to cause chronic diseases (senescence cells ~ so many accumulated mutations)

• Senolytic drug postpone age-associated pathologies in humans

Future perspectives ~ development interventions through DNA repair

Few molecules - may directly stimulate DNA repair

• RAD51-stimulatory compound 1 (RS-1) -- increase HR

• Nicorandil -- stimulate base excision repair through APE1 enzyme

• Aspirin - -- stimulate NER

Modulation of DNA damage response -- impact aging

• Inhibition of PARP1 -- lifespan extension in certain model organisms

• Age-associated activation of PARP1 -- relate to persistent DNA damage foci -- 53BP1, gH2AX, FOXO4 in aging cells

Keys

• NAD+:NADH ratio

• Energy sensor (AMP-AMPK)

Outstanding questions --

A large gap between biochemistry and clinical phenotypes

• Much information in mechanistic but could not well-explain clinical outcomes

(I think a major problem is the ecosystem to support communication between clinicians and researchers).

Do small-molecules DNA repair stimulators attenuate aging?

Does decreasing DNA repair efficacy explain variability in aging phenotypes?

• DNA repair declined with age

• No clear connection between tissue specific vs DNA repair efficacy decline

• No clear connection between age-associated phenotypes vs DNA repair efficacy decline

How the heck can we measure DNA repair stimulators at a clinical level? -- > functional markers, I think