The Gut Microbiome Changes Shortly Before Death in Centenarians

Extremely old people have such high mortality rates that studies such as this one here become practical, answering the question of how the gut microbiome changes in the final decline into death. It is well established that the gut microbiome is influential on health, and undergoes detrimental changes across the course of adult life, although it remains to be determined as to which of the possible mechanisms are most important. In particular, it is unclear as to whether gut microbiome changes provoke inflammatory immune dysfunction or whether age-related immune dysfunction allows more inflammatory microbes to prosper. Or whether both directions of causation are relevant.

Several studies have revealed certain unique characteristics of gut microbiome in centenarians. We established a prospective cohort of fecal microbiota and conducted the first metagenomics-based study among centenarians. The objective was to explore the dynamic changes of gut microbiota in healthy centenarians and centenarians approaching end of life and to unravel the characteristics of aging-associated microbiome. Seventy-five healthy centenarians participated in follow-up surveys and collection of fecal samples at intervals of 3 months. Data pertaining to dietary status, health status scores, cause of disease and death, and fecal specimens were collected for 15 months.

Twenty participants died within 20 months during the follow-up period. The median survival time was 8-9 months and the mortality rate was 14.7% per year. The health status scores before death were significantly lower than those at 3 months before the end of the follow-up period. At this time, the participants mainly exhibited symptoms of anorexia and reduced dietary intake and physical activity. Metagenomics sequencing and analysis were carried out to characterize the gut microbiota changes in the centenarians during their transition from healthy status to death.

Analysis showed a significant change in gut microbiota from 7 months prior to death. All participants were grouped with 7 months before death as cut-off; no significant difference in α diversity was found between the two groups. Analysis revealed significant changes in the abundance of ten bacterial species before death; of these, eight species were significantly reduced (Akkermansia muciniphila, Alistipes finegoldii, Alistipes shahii, Bacteroides faecis, Bacteroides intestinalis, Butyrivibrio crossotus, Bacteroides stercoris, and Prevotella stercorea) while two were significantly increased before death (Bifidobacterium longum and Ruminococcus bromii). We speculate that these changes might occur before the clinical symptoms of deterioration in health status.



- Seventy-five healthy centenarians participated in follow-up surveys.
- Twenty participants died within 20 months during the follow-up period.
- The median survival time was 8-9 months.

Not sure I understand - perhaps someone has seen the whole article?
If median survival is 8-9 months, then how is it possible than only 20 participants, so around 30%, died in the first 20 months?

Posted by: Barbara T. at August 11th, 2020 8:43 AM

Barbara, I did not read it either but it seems likely they would have filtered out those that were obviously already in a death spiral, thus increasing the mean life expectancy significantly.

As far as the cause and effect, I think the question the researchers should have asked is what Deficiency might the microbiome be compensating For, and take the appropriate blood work to confirm.

Posted by: JohnD at August 11th, 2020 11:21 AM

@John D. If anything life expectancy has decreased, not increased. Median survival means that 50% of a cohort is dead at a certain date. So many more than 20 out of 75 participants should have died within 20 months, since according to the article's claim about median survival, 37 or 38 individuals lived less than 8-9 months (I love how they didn't even bother calculating an exact figure) from their baseline test.
The only explanation I can think of is that: X+Y=37 and X people died within 8-9 months of their personal baseline during the initial 15 months of data collection; Y died between month number 1 and month number 9 of the 20 months follow up period; and then, presumably, Z died between month number 10 and month number 20 of the 20 months follow up period. Either way, we have no idea of how many of the participants died - it can't be 20 as the abstract implies - and while this may not be important for the purpose of the study, shoddy reporting is a bad sign.

Posted by: Barbara T. at August 11th, 2020 2:30 PM

Hi there! Just a 2 cents.

''With the 10 differential bacterial species, PCR validation analysis was performed on those centenarians who had successfully collected feces samples before and after 7 months (n = 17).''

It may possible that some of the other centenarians were discarded from the study (due to not collecting feces, (for biopsy) during the period/study, correctly; they are not (necessarily) dead/maybe still alive, they were 75 of them; thus, some discarded as results; 17 out of 75 collected them). Thus, a bunch of them/their results were simply not taken into account. The researchers can't make any study/results if no feces (need bacterias/sample for research/study/results).

''The exclusion criteria were: (1) results of health examination do not qualify the health criteria; (2) Refusal of patients or their families to cooperate; (3) patients with loss of contact in five cycles of follow-up.''

3, some may have loss contact - during the study, not just before (the person may have died during the study - or - did not follow through....they say exclusion critera; but if cuold have been kept during the study too/excluding results of some). Thus, it may mean disqualification/discarding of people result/sample.

''A total of 146 centenarians from Hainan province participated in the baseline multidisciplinary assessment of health status....Excluding clear diseases, the results of physical examination are healthy (Tables 1, 2). Seventy-five healthy centenarians without any of the clear diseases were selected for this study.''

146...down to 75, excluded nearly half...but more excluding during 'on-going' study (for other reasons, such as, not collecting feces (needed -to do the study).

I'm just guessing roughly from reading the methods.

''In particular, it is unclear as to whether gut microbiome changes provoke inflammatory immune dysfunction or whether age-related immune dysfunction allows more inflammatory microbes to prosper. Or whether both directions of causation are relevant.''

I believe it is a combination of both...

''while two species were significantly enriched before death (Bifidobacterium longum and Ruminococcus bromii). ''

B. longum and bifidobacterias are popular 'bacterias' cultures in yoghourt...studies that had 'transfer of gut flora' to a young sick person saw reduction of inflammation/disease...such as a healthy centenarian's gut flora -> given to a young person that is sick. There was improvement in health in the young sick person.

They saw these bacterials changes in the centenarian's gut flora 7 months before they means 1 of 2 things - or - Both things.

1. The immune system is entering immunoscenescence (115 year old woman with small leukocytes white blood cell telomeres -> immunoscenescen). Thus, this 'invites' pathoges/deleterious bacterias -> buffet haven of dangerous bacterias that produce toxins (TMAO; oxides that roam around the blood and contribue to diseases - due to these bacterias forming these toxins/oxidative molecules that wreeak damage on the entire vasculature/ECM....and I'm sure cause DNA DDR/telomere attrition acceleration via inflammation/DDR activation.

2. They say they were me that is the advanced state of death/near death...diseases can make you become frail, loss of bone mineral density (osteoporosis), loss of 'fat mass' (including BAT/WAT, brown/white adiopse tissue), loss of muscle mass - sarcopenia, brain pruning,...akin to Extreme CR/ might slow aging, but you can create anorexia and cause Lack of nutrients/calories; yes, Lack, of supercentenarians, it is as if, they are doing CR...because living this ingesting low calories (Hainan centenarians - 1000 calories/day), they sustain a thin/health body, but Too Much is just as bad; in that old age; food might not 'get in' anymore; yet, you Need it, thy are frail/sarcopenia, you need energy...Low ATP...senescence. It's the same that happened with my mom and me; mother had cancer and chemotherapy made her lose 100 lbs...down to 90lbs...(she weighted 160-170lbs before and measured 5'3, she died weighting 90lbs)...I lost 50 lbs due to atherosclerosis (I was 150 down to 100 due to the disease...not just fat/obese people 'that gain' weight get atherosclerosis - thin ones too if they clog their arteries with LDL fat depot); when you lose precipitously lots of mass 'unexpectedly', without changing any habits - that is the sign of death coming. It,s why it'S crucial to 'maintain' a healthy weight/body - for whole life; with the least 'dips' and 'up/downs'....studies showed that Obesity = accelerated epigenetic aging; anorexia, same thing, it will cause accelerated aging; it is akin to HGPS (Hutchinson-Guilford Progeria Syndrome) people that may be very frail/thin...they live only 15 years (they lose telomerse 10 times faster then regular 'fatter' humans - that maintain theiy Normal weight and have correct chromosomal function/assembly in the cells (Lamin a/progerin/histone)). Humans must be a 'balance' or else, unbalance = unviable for life.

It is stranger to see taht in centenarians, from their intestinal flora, 7 months before death, there is increase in take is that this is a try to curb loss of other bacterias that are positive; while there will be an accumulation of deleterious ones (namely, ones that produce TMAO), while the health bacterias that form SCFAs - will go; Bifidobacterias create colon SCFAs (pyruvate, propionate, butyrate...); these help tremendously to lose weight, make anti-inflammation, force the body to become ketotic/burn fat as energy (instead of relying on glucose for energy/fuel); that the B. Longum would Increase Before means compensation to try to mitigate the failing/immuniosenescent immune system. They lose a large chunk of bacterias (possibly many healthy/anti-inflammation-elements producing ones in that lot); it's nearly 100% sure realted to immune loss - since immunity system is Needed for cancer/pathogen/bacterial - killing...the 'bacterias' 'take over'....the bad ones/inflammatory may be a case of bacterial overload (there is just too much deleterious bad bacterias - excess inflammation) or bacterial loss (they lose lots of 'types' of (good) bacterias...and thus, not much protection left).

If there is an excess of negative bacterias -> strong inflammation, strong production of oxidizing Toxins (TMAO), acceleration of ROS at mitos -> acceleration of telomere loss/short telomeres in immune leukocytes (as seen in 115 old woman). Destruction of the colon/intestin -> impossible to digest/loss of immunity -> pathogen haven/infection/cancer...etc..incompatible/no more immunity.

Just a 2 cents.

Posted by: CANanonymity at August 11th, 2020 5:22 PM

@CANanonymity: Thanks!

Posted by: Barbara T. at August 12th, 2020 4:31 AM

You're Welcome Barbara.

Posted by: CANanonymity at August 12th, 2020 9:50 PM
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