Methods for in vitro investigating mitochondrial replication dysfunction in a biological sample, kits and uses thereof, therapeutic methods against progeroid-like syndromes or symptomes and screening method for identifying particular protease inhibitor(s) and/or nitroso-redox stress scavenger compound(s)

A method for restoring POLG1 levels in a patient in need thereof to treat or delay physiological ageing or physiopathological ageing, or accelerated ageing or a progeroid syndrome, or neurodegenerative disorders or symptoms thereof, comprising administering to a patient in need thereof a protease inhibitor which interacts with protease(s) degrading POLG1.

A method to treat or delay physiological ageing or physiopathological ageing, or accelerated ageing or a progeroid syndrome, or symptoms thereof, and/or to restore the level(s) of protein(s) selected in the group of:

• HTRA2, HTRA3 and POLG1, or combinations thereof, comprising administering to a patient in need thereof at least one nitroso-redox stress scavenger compound.

A method to treat or delay physiological ageing or physiopathological ageing, or accelerated ageing or a progeroid syndrome, or neurodegenerative disorders or symptoms thereof, and/or to restore the level(s) of at least one protein selected from HTRA2, HTRA3 and POLG1, comprising administering to a patient in need thereof a protease inhibitor which interacts with protease(s) degrading POLG1 in combination with a nitroso-redox stress scavenger compound.

An in vitro process for screening protease inhibitor(s) for identifying protease inhibitor(s) capable of restoring POLG1 level in a cell, and/or for screening nitroso-redox stress scavenger compound(s) for identifying nitroso-redox stress scavenger compound(s) capable of restoring POLG level in a cell, comprising the steps of:

• i. contacting a cell or a cell culture, having a decreased level of POLG1 by at least 10% with respect to a normal threshold value determined for cells characteristic of healthy subject(s) with a marker specifically recognizing POLG1,
• ii. contacting said cell(s) with protease inhibitor(s) and/or nitroso-redox stress scavenger compound(s) to assay, wherein steps i. and ii. can be inverted, and
• iii. measuring and/or visualizing the change(s) in the level of POLG1 of the cell(s) contacted in steps i. and ii.