Research in Dr. Passos' Cell and Molecular Aging Laboratory at Mayo Clinic is focused on the role of senescent cells in aging and age-related disease, with a particular focus on the role of mitochondria and telomeres in the process.
Telomere damage as a biomarker of aging
Telomeres are key drivers of cellular senescence. When damaged or critically short, telomeres elicit a persistent DNA damage response that drives senescence.
Dr. Passos' research team has shown that telomere-associated DNA damage foci (TAF), indicating co-localization between DNA damage response proteins and telomeres, increases during aging in a variety of tissues such as skin, liver, intestine, lung, heart, muscle, brain and bone. The Cell and Molecular Aging Lab has also observed increased TAF in lung diseases such as chronic obstructive pulmonary disease, bronchiectasis and idiopathic pulmonary fibrosis. Increased TAF occurs in nonalcoholic and alcoholic liver disease and myocardial infarction as well. Research has shown that TAF can be induced by factors known to accelerate the aging process such as inflammation, obesity, mitochondrial dysfunction and impaired autophagy.
Furthermore, Dr. Passos' research team has shown that interventions that extend a person's health span, such as rapamycin sirolimus, dietary restriction, 17α-estradiol or senolytics, also significantly reduced TAF during aging.
Based on extensive data accumulated over several years, the research team has proposed that TAF is a much more robust marker of cellular senescence in vivo than others commonly used. Dr. Passos' lab is proposing the use of TAF in clinical practice as a prognostic tool to measure biological age as well as efficacy of treatments.
- Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ognodnik M, Jurk D, Proctor C, Correia-Mela C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens A, Greaves LC, Kolsky KL, Parini A, Douin-Echinar V, LeBrasseur NK, Arthur HM, Tual-Chalot S, Schafer MJ, Roos CM, Miller JD, Robertson N, Mann J, Adams PD, Tchkonia T, Kirkland JL, Mialet-Perez J, Richardson GD, Passos JF.
Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. The EMBO Journal. 2019;38:5.
- Hewitt G, Jurk D, Marques F, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nature Communications. 2012;3:708.
To accurately measure and visualize telomere dysfunction in multiple tissues, the Cell and Molecular Aging Lab has optimized different methods using both conventional fluorescent microscopy and super-resolution microscopy. Additionally, Dr. Passos' lab developed computer imaging software to quantify telomere dysfunction in different cells and tissues in an unbiased and reliable manner. Dr. Passos and his team continue to work toward the development of novel methods and analysis tools to investigate telomeres and senescence in tissues.
Mitochondria and aging
The Cell and Molecular Aging Lab's research shows that there is a key role for mitochondria in senescent cells. The lab has developed a protocol to generate mammalian cell populations with low to nondetectable levels of mitochondria and culture conditions allowing the maintenance of mitochondrial-depleted cells for up to 30 days with minimal loss of viability. This methodology enables the research team to conduct a proof-of-principle experiment to demonstrate the involvement of mitochondria in cellular senescence.
- Correia-Melo C, Ichim G, Tait S, Passos JF. Depletion of mitochondria in mammalian cells through enforced mitophagy. Nature Protocols. 2017;12:183.
- Correia-Mela C, Marques F, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait S, Czapiewski R, Greaves, L Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF. Mitochondria are required for pro-ageing features of the senescent phenotype. The EMBO Journal. 2016;35:724.
Dr. Passos' research team is investigating the molecular processes by which mitochondria drive senescence with the hope of finding new therapies to improve health during old age. The team is also conducting drug screens targeting mitochondrial function to find new therapies to counteract the aging process.