One of the most disturbing symptoms that occur with aging is rigidity. Humans become stiffer with age, not only in mentality but also physically. Flexibility is in short supply with age as fibroblasts get activated for any tiny injury and respond by excessively depositing extracellular matrix components. For this reason alone, fibrosis – especially excessive one – should be targeted by anti-aging drugs.
Healing injuries with scars doesn’t happen in all organisms. For example, organisms having only a native immune system are able to completely regenerate some or all of their tissues when injured.
This is not the case with humans. We have an innate immune system and an adaptive one. We not only attack intruders as they come but we also remember them. We have this thing called immunological memory. This is why we form antibodies and why vaccines work in preventing infectious diseases or at least complications of such infections. Antibodies are great for surviving infections but all this added complexity made complete regeneration a thing of the past for all vertebrates, humans included.
Scars are better than no healing at all. Yet those scars can form in excessive quantity with age (from multiple lesions and from worse healing abilities with time) and the ensuing rigidity can be very uncomfortable hence this blog post where I propose the use of current and future antifibrotic drugs with the purpose of slowing down aging and making it more bearable.
There are several clinical trials worldwide targeting fibrosis in diverse pathologies, most of them age-related diseases. Unfortunately, many times the endpoint in such trials is a certain organ dysfunction which appears after fibrosis replaces normal tissue. This is unfortunate as antifibrotic drugs may limit the formation of scars when started early but the endpoint wouldn’t be modified if the therapy is started too late when little functional tissue is left.
For this reason, it is preferable for anti-aging purposes to:
- Minimize injuries that lead to scar formation
- Use antifibrotic drugs early on before fibrosis replaces most normal tissue
- Use regenerative medicine or even artificial devices when there is barely any normal tissue left.
Minimize injuries and inflammation that lead to scar formation
We can’t prevent all injuries. Accidents will always happen. But the injuries that we suffer from during our lives are responsible for how likely we are to age gracefully.
For example, consistent exercise can minimize the risk of age-related metabolic syndrome but not all exercise is equal. Some sports make individuals very prone to injuries. Some physical activities – at home or during a job or hobby – are riskier and some are less so. My favorite sport remains swimming which I do once per week. I’d swim every day if I could but at this life stage that’s almost impossible. I still had some minor accidents while swimming but nothing like I’d have if I tried more violent sports. As for activity-prone injuries related to a job or a hobby, some of those can be avoided simply by using a better tool.
Another source of daily injuries we can avoid is through diet. For avoiding dietary AGE products, you can also check out a previous blog post I wrote here. Avoiding alcohol, smoking and drugs also minimizes the number of injuries your body has to deal with every day. Whether related to lifestyle or not, obesity leads to many tiny injuries which add up in time.
Use antifibrotic drugs early on before fibrosis replaces most normal tissue
There are already a couple of antifibrotic drugs on the clinical market. None of them is recommended for aging specifically but except for absolute or relative contraindications on a case by case basis, all of them are recommended as early as possible after diagnosis of said disease.
The major problem with administering such medication is the reactivation of old infections whereby fibrosis limited the spread of such microorganisms throughout the body, especially if there is some associated immunosuppresion because of the disease itself, because of the antifibrotic medication or because of some other medication necessary for such disease.
Most diseases where fibrosis reduces quality of life start with inflammation so the prescription of corticosteroids – which are anti-inflammatory and which cause immunosuppression to varying degrees depending on the route of administration – is often encountered. Infections that could be reactivated this way include B and C hepatitis and tuberculosis. Such infections could be asymptomatic. For this reason, diagnostic tests to check for at least these 3 microorganisms are necessary before trying any antifibrotic drug.
According to this excellent review paper, drugs which limit the formation of fibrosis act on several metabolic pathways, most of them involved in aging too:
Extracellular factors
- Growth factors: TGF beta, VEGF, TNF
- Cytokines
- MMP/TIMP
- Other proteins and peptides: angiotensin II
Intracellular factors
- Enzymes: mTOR, JAK-STAT, NF-kB
- Nuclear receptors: PPAR
- Other proteins
- Epigenetics: mRNA, methylation
Extracellular and intracellular factors:
- LOX
- ROS
Although many of these targets can be inhibited by calorie restriction (growth factors, mTOR, PPAR etc.), several antifibrotic medications act on them too.
Out of all the medications mentioned in the review, I think the most promising for early anti-aging intervention is losartan which is currently prescribed for hypertension while being tested for liver fibrosis and cystic fibrosis. Losartan acts as an antagonist to angiotensin II. Since blood pressure can easily be monitored, this drug could be used after midlife in small doses if blood pressure increases above the maximum optimum value of 120/80 mmHg but clinical studies are needed to see whether this increases lifespan as well.
Dasatinib was also an interesting mention since it acts as a senolytic but it also blocks VEGF thereby minimizing scar formation. The drug is currently tested as an antifibrotic drug in pulmonary scleroderma.
Thalidomide is a very old medication and up until this review, I didn’t know it acted by inhibiting TNF. Although acting as an antifibrotic drug, I don’t see it used widely to prevent age-related fibrosis, at least not in women of fertile age. Dasatinib and losartan should also not be used in such cases.
Many other drugs mentioned in the same review paper are drugs frequently prescribed in geriatric wards:
-monoclonal antibodies used for cancer and autoimmune diseases
-pentoxifylline used for peripheral artery disease
-N-acetylcysteine used as a mucolytic drug
-rapamycin/sirolimus to prevent transplant rejection
Finally, some antifibrotic substances mentioned in the referenced review are substances which can be had from food and dietary supplements :
-curcumin
-silymarin
-DHA (docosahexaenoic acid)
-genistein
-glycyrrhizin
-baicalein
-salvianolic acid B
-resveratrol
-vitamins like pyridoxamine (B6), alpha-tocopherol (E)
-several traditional Chinese medicine therapies (usually herb mixes)
-Ginkgo biloba extract (acting on TGF-beta)
By checking how each of the above substances act, you may recognize a common pattern of antifibrotic drugs minimizing growth and inflammation. To some extent, the latter can also be reduced by practicing calorie restriction and consistent exercise. These can’t by themselves avoid or cure aging but they are reasonable measures to age gracefully.
Use regenerative medicine or even artificial devices when there is barely any normal tissue left.
Although lifestyle measures and early use of antifibrotic drugs have some value, there comes a point when fibrosis replaces most of the normal tissue and only replacing the diseased tissue with a new, healthy one or even with an artificial device could allow the continuation of life as we know it: flexible and easy to move and think.
References
Li, Xiaoyi, Lixin Zhu, Beibei Wang, Meifei Yuan, and Ruixin Zhu. “Drugs and targets in fibrosis.” Frontiers in pharmacology 8 (2017): 855.
Anca Ioviţă is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, don’t forget to sign up to receive updates on longevity news and novel book projects!
Don’t miss out on the Pinterest board on calorie restriction with optimal nutrition where she pins new recipes every day.
https://www.pinterest.com/longevityletter/eat-less-live-longer/
Or the Comparative Gerontology Facebook Group where you can join the discussions on how species age at different speeds and what could be the mechanisms underlining these differences!
https://www.facebook.com/groups/683953735071847/
